Indole derivatives

ABSTRACT

This invention is directed to a indole derivative represented by the general formula (1) ##STR1## wherein R 1  stands for alkyl of 1 to 5 carbon atoms, cycloalkylalkyl of 4 to 7 carbon atoms, cycloalkenylalkyl of 5 to 7 carbon atoms, aralkyl of 7 to 14 carbon atoms, trans-alkenyl of 4 to 5 carbon atoms, allyl, furanyl-2-ylalkyl of 1 to 5 carbon atoms, thienyl-2-ylalkyl of 1 to 5 carbon atoms, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, alkanoyl of 1 to 5 carbon atoms, aralkylcarbonyl of 7 to 14 carbon atoms, 2-furoyl, thiophene-2-carbonyl, cycloalkylcarbonyl of 4 to 7 carbon atoms, alkenylcarbonyl of 3 to 8 carbon atoms, or anisoyl, R 2  for a hydrogen atoms, alkyl of 1 to 3 carbon atoms, benzyl, or alkanoyl of 1 to 5 carbon atoms, R 3  for a hydrogen atoms, a fluorine atom, a chlorine atom, a bromine atom, nitro, or alkyl of 1 to 5 carbon atoms, R 4  for a hydrogen atom, alkyl of 1 to 5 carbon atoms, benzyl, or phenyl, and R 5  for a hydrogen atom, hydroxy, or alkanoyloxy of 1 to 5 carbon atoms, providing that said general formula (1) embraces a (+) form, a (-) form, and a (±) form, or a pharmacologically acceptable salt thereof and to an immunorepressing agent having as an active component thereof the indole derivative or the pharmacologically acceptable salt thereof.

TECHNICAL FIELD OF THE INVENTION

This invention relates to a compound having an affinity for thedelta-opioid receptor. The delta-opioid receptor is concerned in theanalgesic, immune, and circulatory (particularly blood pressure)systems. Ligands having high selectively for the receptor are usable asmedicines like analgesics, immunosuppressants, immunopotentiatingagents, and antihypertensive agents.

BACKGROUND OF THE INVENTION

The delta opioid receptor is possessed of many pharmacological actionsas described above. Compounds having high selectively for this receptorpromise adoption as analgesics, immunosuppressants, immunopotentiatingagents, and antihypertensive agents. Except for peptide type compounds,no ligand of high selectivity for the delta receptor has been discovereduntil recent years. The peptide type compounds have not easily permittedtheir own development as the medicines mentioned above because they havethe fault that they encounter difficulty in passing the blood-brainbarrier with yield easily to in vivo decomposition with peptidase. Thus,agonists and antagonists possessed of high selectivity for the deltareceptor are in demand. Recently, Portoghese et al have discovered anantagonist, NTI, possessed of high selectivity for the delta-opioidreceptor (P. S. Portoghese et al., J. Med. Chem., Vol. 31, No. 2, 1988).This NTI is an alkaloid and, unlike peptides, is free from the problemof passage through the blood-brain barrier and the problem ofdecomposition with a peptidase. The NTI, however, is problematic inrespect that the cost of its production is high because it issynthesized from naltrexone as a raw material and the naltrexone isdifficult to procure because it is synthesized from thebaine which is anarcotic. As regards delta receptor agonists, peptides such as DADLE andDPDPE have been known in the art. Alkaloids of high selectivity remainto be developed.

An object of this invention is to provide a ligand (agonist andantagonist) which has a high affinity and selectivity for the deltareceptor promising to manifest the aforementioned pharmacologicalactions, attains synthesis of its own through a route not using anarcotic as a raw material, passes through the blood-brain barrier,enjoys high stability in resisting a peptidase, and is not excessivelyexpensive.

DISCLOSURE OF THE INVENTION

To accomplish the object described above, this invention is constructedas follows.

To be specific, this invention is directed to an indole derivativerepresented by the general formula (1): ##STR2## wherein R₁ stands foralkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbonatoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to14 carbon atoms, trans-alkenyl having 4 or 5 carbon atoms, allyl,furanyl-2-ylalkyl having 1 to 5 carbon atoms, thienyl-2ylalkyl having 1to 5 carbon atoms, vinyloxycarbonyl, trichloroethoxycarbonyl,benzyloxycarbonyl, alkanoyl having 1 to 5 carbon atoms, aralkylcarbonylhaving 7 to 14 carbon atoms, 2-furoyl, thiophene-2-carbonyl,cycloalkylcarbonyl having 4 to 7 carbon atoms, alkenylcarbonyl having 3to 8 carbon atoms, or anisoyl, R₂ stands for a hydrogen atoms, alkylhaving 1 to 3 carbon atoms, benzyl, or alkanoyl having 1 to 5 carbonatoms, R₃ stands for a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, nitro, or alkyl having 1 to 5 carbon atoms, R₄ standsfor a hydrogen atom, alkyl having 1 to 5 carbon atoms, benzyl, orphenyl, and R₅ stands for a hydrogen atom, hydroxy, or alkanoyloxyhaving 1 to 5 carbon atoms, or a pharmacologically acceptable saltthereof.

As pharmacologically desirable salts, inorganic salts such ashydrochloride, sulfate, hydrobromide, and phosphate, and organic saltssuch as acetate, lactate, methanesulfonate, p-toluenesulfonate,phthalate, fumarate, maleate, glutarate, and tartrate may be mentionedfor example. Of course, these salts are not exclusive examples.

In the general formula (1), R₁ stands for methyl, ethyl, propyl, butyl,pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, allyl,2-furanylmethyl, 2thienylmethyl, trans-2-butenyl, cycloproylcarbonyl,2,2,2-trichloroethoxycarbonyl, or vinyloxycarbonyl, R₂ stands for ahydrogen atom, methyl, ethyl, propyl, benzyl, acetyl, propanoyl,butanoyl, or pentanoyl, R₃ stands for a hydrogen atom, a fluorine atom,a chlorine atom, a bromine atom, nitro, methyl, ethyl, propyl, butyl, orpentyl, R₄ for a hydrogen atom, methyl, ethyl, propyl, butyl, pentyl,phenyl, or benzyl, and R₅ stands for a hydrogen atom, hydroxy, acetoxy,propanoyloxy, butanoyloxy, or pentanoyloxy, for example. Preferably, R₁stands for methyl, cyclopropylmethyl, cyclobutylmethyl, allyl,2-furanylmethyl, cyclopropylcarbonyl, 2,2,2-trichloroethoxycarbonyl, orvinyloxycarbonyl, R₂ stands for a hydrogen atom, methyl, acetyl, orbenzyl, R₃ stands for a hydrogen atom, a fluorine atom, a chlorine atom,a bromine, or methyl, R₄ stands for a hydrogen atom, methyl, or benzyl,and R₅ stands for a hydrogen atom, hydroxy, or acetoxy, for example.

In the compounds of this invention represented by the general formula(1), the particular compound having methyl as R₁ and hydrogen atoms eachfor R₂, R₃, R₄, and R₅ (Formula 2) is named2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline.##STR3##

In accordance with the nomenclautre exemplified above, as representativeexamples of the compound of the present invention,2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3 -hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl--indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2methyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2allyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2allyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydrophenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]croquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indro[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-8-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopylmethyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[ 2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4-aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4-aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4-aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4-aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4-aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβoctahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3hydroxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-hydroxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,may be cited. Of course, these compounds are not exclusive examples.

This invention further provides an isoquinoline derivative, which is anintermediate for the production of the compound of this inventionrepresented by the formula (1) and is represented by the formula (101):##STR4## wherein R₁₀₁ stands for a hydrogen atom, alkyl having 1 to 5carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,cycloalkenylalkyl having 6 to 8 carbon atoms, aralkyl having 7 to 14carbon atoms, trans-alkenyl having 4 to 5 carbon atoms, allyl,furanyl-2-ylalkyl, thienyl-2-ylalkyl, R₁₀₇ OCO (wherein R₁₀₇ stands for2,2,2-trichloroethyl or benzyl), or R₁₀₈ CO (wherein R₁₀₈ stands foralkyl having 1 to 5 carbon atoms, cycloalkyl having 3 to 6 carbon atoms,cycloalkenyl having 5 to 7 carbon atoms, phenyl, aralkyl having 7 to 13carbon atoms, trans-alkenyl having 4 or 5 carbon atoms, vinyl,2-furanyl, or 2-thienyl), and R₁₀₂, R₁₀₃, R₁₀₄, and R₁₀₅ independentlystand for a hydrogen atom, hydroxy, alkanoyloxy having 1 to 5 carbonatoms, or alkoxy having 1 to 5 carbon atoms, providing that R₁₀₂ andR₁₀₃ or R₁₀₃ and R₁₀₄ may form an oxo group and R₁₀₃ and R₁₀₄ mayjointly form a 1,3-dioxolane ring, and R₁₀₆ stands for a hydrogen atom,hydroxy, alkoxy having 1 to 5 carbon atoms, or alkanoyloxy having 1 to 5carbon atoms, or a pharmacologically acceptable salt thereof and amethod for the production thereof.

The salts which are pharmacologically acceptable for use in thisinvention include salts with such inorganic acids as hydrochloric acid,hydrobromic acid, sulfuric acid, and phosphoric acid and salts with suchorganic acids as acetic acid, lactic acid, oxalic acid, succinic acid,methanesulfonic acid, benzene-sulfonic acid, toluenesulfonic acid,fumaric acid, maleic acid, and tartaric acid, for example.

Of the isoquinoline derivative represented by the general formula (101),those which prove to be particularly desirable are such that R₁₀₁ standsfor methyl, ethyl, propyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl,phenylpropyl, trans-butenyl, allyl, furanyl-2-ylmethyl,thienyl-2-ylmethyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl,acetyl, cyclopropanecarbonyl, cyclobutanecarbonyl,cyclopentenecarbbonyl, benzoyl, phenylacetyl, trans-propenylcarbonyl,acryloyl, 2-furanylcarbonyl, or 2-thienylcarbonyl, R₁₀₂, R₁₀₃, R₁₀₄, andR₁₀₅ independently stand for hydrogen atom, hydroxy, acetoxy, ormethoxy, providing that R₁₀₂ and R₁₀₃ as a pair, and/or R₁₀₄ and R₁₀₅ asa pair may form an oxo group or R₁₀₃ and R₁₀₄ may jointly form a2,2-dimethyl-1,3-dioxolane ring, and R₁₀₆ represents for example, ahydrogen atom, hydroxy, methoxy, or acetoxy. These substituents are notexclusive examples.

Further, the isoquinoline derivatives which as represented by thefollowing general formulas (101b) and (101c): ##STR5## wherein R₁₀₁ andR₁₀₆ have the same meanings as defined above having a ketone group atthe 6 position and/or the 7 position prove to be particularly desirable.

In the compounds of this invention represented by the general formula(101), the particular compound (106) wherein R₁₀₁ is methyl, R₁₀₂ andR₁₀₃ are a hydrogen atom R₁₀₄ and R₁₀₅ are in oxygen atom, and R₁₀₆ ismethoxy: ##STR6## is named2-methyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.In accordance with the nomenclature exemplified above, as representativeexamples of the compound of this invention,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-methyl-4aα-(3-methoxyphenyl)-6,7-dioxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6,7-dioxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6,7-dioxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-6,7-dioxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-allyl-4aα-(3-methoxyphenyl)-6,7-dioxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-methyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-allyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-methyl-4aα-(3-methoxyphenyl)-6,7,8aβ-trihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,3cyclopropylmethyl-4aα-(3-methoxyphenyl)-6,7,8aβ-trihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6,7,8aβ-trihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-6,7,8aβ-trihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-allyl-4aα-(3-methoxyphenyl)-6,7,8aβ-trihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6acetoxy-8a.beta.-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyloxycarbonyl-4aα-(3methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzoyl-4a-(3-methoxyphenyl)-6acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenylacetyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-acryloyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinoline,2-benzyloxycarbonyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinoline,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinoline,2-benzoyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinoline,2-phenylacetyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinoline,and2-acryloyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolinemay be cited. Of course, these compounds are not exclusive examples.

The compounds of this invention embrace (+), (-), and (±) forms.

The compounds of this invention represented by the general formula (1)are produced easily by treating the corresponding compounds representedby the general formula (3) to react with amine derivatives representedby the general formula (4) in a solvent in the presence of an acidcatalyst (Chart 1) [wherein R₁, R₂, R₃, R₄, and R₅ have the samemeanings as defined above].

The solvents which are usable for the reaction include alcohols such asmethanol and ethanol, fatty acid solvents such as acetic acid andpropionic acid, and dipolar aprotic solvents such as DMF and DMSO, forexample. Among other solvents mentioned above, alcohols prove to bedesirable and ethanol is particularly desirable. As amine derivativesrepresented by the general formula (4), phenylhydrazine derivatives arecited. The acid catalysts which are usable effectively herein includeinorganic acids such as hydrochloric acid, sulfuric acid, nitric acid,and phosphoric acid and organic acids such as methanesulfonic acid,p-toluenesulfonic acid, acetic acid, formic acid, and propionic acid,for example. Among other acids mentioned above hydrochloric acid,sulfuric acid, and methanesulfonic acid are desirably used. Of course,these acids are not exclusive examples. The reaction temperature isconceivable in the range of from 0° C. to 300° C. The reaction ispracticable at temperatures in the range of from 25° C. to 150° C.Generally, the reaction is carried out favorably at temperatures in therange of from 60° to 120° C.

Of the compounds represented by the general formula (1), those of ageneral formula (1') having a hydrogen atom as R₂ are obtained bydissolving the corresponding compounds of the general formula (1) havingmethyl as R₂ in a solvent and causing the dissolved compounds to reactwith a base in the presence of mercaptan or to react with a trivalentboron compound (in the formulas, R₁, R₃, R₄, and R₅ have the samemeanings as defined above). In the reaction using mercaptan and a base,such dipolar aprotic solvents as DMF, DMSO and HMPA are favorably usableand DMF is used particularly desirable. In the reaction using trivalentboron compound, halogenous solvents such as methylene chloride,chloroform, and carbon tetrachloride are favorably usable and methylenechloride is used particularly desirable. As mercaptans which areeffectively usable in the reaction, those mercaptans possessed of a sidechain having 1 to 10 carbon atoms may be cited. Generally, propylmercaptan is desirably used. The bases which are effectively usableherein include alkali metal salts of alcohols such as potassiumt-butoxide, potassium ethoxide, potassium methoxide, sodium t-butoxide,sodium ethoxide, and sodium methoxide, metal hydrides such as sodiumhydride and potassium hydride, and metal salts of ammonia such as sodiumamide, for example. Generally, the reaction using potassium t-butoxideyields fully satisfactory results. As trivalent boron compoundseffectively usable herein, boron tribromide and boron trichloride may becited. Boron tribromide proves to be particularly desirable. Thereaction temperature when the reaction uses a mercaptan is conceivablein the range of from 0° C. to 300° C. and is desirable in the range offrom 50° C. to 200° C. This reaction performed at temperatures in therange of from 100° C. to 160° yields fully satisfactory results. In thereaction using a trivalent boron compound, the reaction temperature isdesired in the range of from -80° C. to 50° C., preferably from 0° C. to30° C.

In the compounds of the general formula (3), the particular compoundhaving methyl as R₁ and R₂ and a hydrogen atom as R₅ can be synthesizedin accordance with the method reported by D. M. Zimmerman (J. Org.Chem., 1989, 54, 1442.). ##STR7##

In the compounds of the general formula (1), those having alkyl of 2 to5 carbon atoms, cycloalkylalkyl of 3 to 6 carbon atoms,cycloalkenylalkyl of 5 to 7 carbon atoms, aralkyl, trans-alkenyl of 4 to5 carbon atoms, allyl or furanyl-2-ylalkyl as R₁, methyl as R₂, and ahydrogen atoms as R₄ can be produced through a route indicated in Chart2. The first step resides in converting the methyl group on the nitrogenatom of ketone (3) into a carbamate by the use of a chlorocarbonic esterrepresented by the general formula (5) in the presence of a base. In theformula (5), R₆ stands for a vinyl or trichloroethyl group. The base tobe used in the conversion has a large enough steric hindrance to avoidreacting with an acid chloride. For example, such bases as protonesponge and Hunig base prove to be desirable. As regards the solvent,such halogenous solvents as methylene chloride, chloroform, carbontetrachloride, and 1,2-dichloroethane are favorably usable. Generally,1,2-dichloroethane is desirably used. The reaction temperature ispracticable in the range of from -80° to 100° C. Generally, the reactionperformed at temperatures in the range of from 0° C. to normal roomtemperature yields satisfactory results. The second step resides inproducing a compound represented by the general formula (7) by the useof a reagent represented by the general formula (4) in the same manneras in Chart 1 (the reaction conditions and R₄ and R₃ are identical tothose in Chart 1). The third step resides in deprotection nitrogen atomof a protective group on the nitrogen atom to afford a secondary amine.Where R₆ is a vinyl group, hydrolysis is easily effected by the use ofhydrochloric acid-methanol. The reaction is generally executed at thereflux temperature of methanol. Where R₆ is a trichloroethyl group, theremoval can be effected by virtue of reduction with zinc in the presenceof an acid catalyst. The acids that are effectively usable in thereaction include acetic acid, hydrochloric acid, sulfuric acid, andnitric acid, for example. Generally, the reaction performed with aceticacid both as solvent and acid catalyst yields fully satisfactoryresults. The reaction can be generally carried out at room temperature.The fourth step resides in producing an amide (10) by the reaction ofthe compound represented by the general formula (8) with an acidchloride in the presence of a base (R₇ stands for alkyl having 1 to 4carbon atoms, cycloalkyl having 3 to 6 carbon atoms, cycloalkenyl having5 to 7 carbon atoms, aryl, transalkenyl having 3 or 4 carbon atoms,vinyl, or 2furanyl and R₃ has the same meaning as defined above). Thebases that are effectively usable in the reaction include tertiaryamines such as triethylamine, diisopropylethylamine, and proton sponge,for example. Generally, the reaction using triethylamine yields fullysatisfactory results. As respects the solvent, such halogenous solventsas dichloromethane, chloroform, and 1,2-dichloroethane are effectivelyusable. Among other solvents mentioned above, dichloromethaneparticularly is favorably used. The reaction can be carried out attemperatures in the range of from -80° C. to 100° C., preferably from 0°C. to 30° C. The fifth step resides in converting the amide, byreduction, into an amine. The reducing agents that are effectivelyusable in the conversion include sodium borohydride, lithium aluminumhydride, DIBAR, and lithium borohydride, for example. Among otherreducing agents mentioned above, DIBAR and lithium aluminum hydrideprove to be particularly desirable. As regards the solvent, such ethersas ether, THF, DME, and dioxane are desirably used. Among other solventsmentioned above, THF proves to be particularly desirable. The reactioncan be carried out at temperatures in the range of from 31 40° C. to100° C., preferably 0° C. to 30° C. The sixth step resides in theconversion into a hydroxide group by the removal of the methyl group.The conversion can be effected under the same conditions as those usedin the production of the particular compound of the general formula (1)having a hydrogen atom as R₂. ##STR8##

In the compounds represented by the general formula (1), those whichhave alkyl of 2 to 5 carbon atoms, cycloalkylalkyl of 3 to 6 carbonatoms, cycloalkenylalkyl of 5 to 7 carbon atoms, aralkyl, transalkenylof 4 to 5 carbon atoms, allyl, or furanyl-2-ylalkyl as R₁ and a hydrogenatom as R₂ and R₅ can be also produced through a route shown in Chart 3.

The first step resides in producing a compound represented by thegeneral formula (6) (R₆ and has the same meaning as defined above). Thereaction conditions involved therein are the same as those of the firststep in Chart 2. The second step resides in deprotection atom aprotective group in the nitrogen and affording a secondary amine. WhereR₆ is vinyl, the hydrolysis can be easily effected with hydrochloricacid-methanol. The reaction is generally carried out at the refluxtemperature of methanol. Where R₆ is a trichloroethyl group, the removalof the protective group can be attained by reduction with zinc in thepresence of an acid catalyst. The acids effectively usable for thecatalysis include acetic acid, hydrochloric acid, sulfuric acid, andnitric acid, for example. Generally, the reaction using acetic acid bothas solvent and catalyst yields fully satisfactory results. The thirdstep resides in producing an amide (13) by the reaction of a secondaryamine (12) with an acid chloride (9) in the presence of a base (R₇ hasthe same meaning as defined above). The bases which are effectivelyusable for the reaction include such tertiary amines as triethylamine,diisopropylethylamine, and proton sponge, for example. Generally, thereaction using triethylamine yields fully satisfactory results. Thesolvents which are effectively usable in the reaction include suchhalogenous solvents as dichloromethane, chloroform, and1,2-dichloroethane, for example. Generally, dichloromethane is favorablyused. The reaction can be carried out at temperatures in the range offrom -80° C. to 100° C., preferably from 0° C. to 30° C. The fourth stepresides in producing a compound represented by the general formula (10)by the use of a reagent represented by the general formula (4) in thesame manner as in Chart 1 (R₃ and R₄ have the same meanings as definedabove). The reaction conditions involved herein are the same as those ofthe second step in Chart 2. The fifth step resides in converting theamide by reduction into an amine and the sixth step in converting theamine into a hydroxyl group by the removal of a methyl group. Thereaction conditions involved in these steps are identical, respectively,to those of the fifth and sixth steps in Chart 2. ##STR9##

In the compounds represented by the general formula (3), those havingalkyl of 2 to 5 carbon atoms, cycloalkylalkyl of 3 to 6 carbon atoms,cycloalkenylalkyl of 5 to 7 carbon atoms, aralkyl, trans-alkenyl of 4 or5 carbon atoms, allyl, or furanyl-2-ylalkyl as R₁, methyl as R₂ and ahydrogen atom as R₅ can be produced through a route shown in Chart 4.The first step resides in converting the methyl group on the nitrogenatom of an acetate (14) into a carbamate by the use of a chlorocarbonicester represented by the general formula (5) in the presence of a base.As R₆, vinyl and trichloroethyl are cited. Trichloroethyl isparticularly desirable. The base to be used is processed of sterichindrance large enough to avoid reacting with the acid chloride.Generally, a proton sponge and Hunig base are used as bases. Thesolvents usable herein include such halogenous solvents as methylenechloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane.Especially, 1,2-dichloroethane is particularly desirable. The reactioncan be carried out at temperature in the range of from -80° C. to 100°C. Generally, the reaction performed at temperature in the range of from0° C. to normal room temperature yields satisfactory results. The secondstep resides in producing a secondary amine (16) by deprotection of aprotective group in the nitrogen atom through reduction with zinc in thepresence of an acid catalyst. The acids include acetic acid,hydrochloric acid, sulfuric acid, and nitric acid. Generally, thereaction using acetic acid both as solvent and catalyst yields fullysatisfactory results. The reaction can be carried out generally at roomtemperature. The third step resides in producing an amide (17) by thereaction of an amine (16) with an acid chloride represented by thegeneral formula (9) (R₇ has the same meaning as defined above). Thereaction can be carried out under the same conditions as those of thethird step in Chart 3. The fourth step resides in producing a compoundrepresented by the general formula (18) by the conversion of an amide byreduction into an amine and an ester to an alcohol. The reducing agentsinclude lithium aluminum hydride, DIBAR, and lithium borohydride, forexample. Among other reducing agents, lithium aluminum hydride and DIBARare particularly desirable. The solvents include such ethers as ether,THF, and DME. Among other solvents, THF is particularly desirable. Thereaction can be carried out at temperatures in the range of from -40° C.to 100° C., preferably from 0° C. to 30° C. The fifth step resides inproducing a ketone (19) by the oxidation of an alcohol (18). Theoxidizing agents include chromic acid, potassium permanganate, DMSO-DCC,and DMSO-oxalyl chloride, for example. Among other oxidizing agents,DMSO-oxalyl chloride is particularly desirable. The solvents includesuch halogenous solvents as dichloromethane and chloroform. Among thesolvents cited above, dichloromethane is particularly desirable. Thereaction can be carried out at temperatures in the range of from -100°C. to 0° C., preferably from -80° C. to -50° C. ##STR10##

In the compounds of the general formula (1), those having a methyl groupas R₁ and a hydroxyl group as R₅ are specifically produced under thefollowing conditions (Chart 5). The first step resides in conversion ofmethyl group on the nitrogen atom in an enamine form (20) synthesizablein accordance with the method reported by D. M. Zimmerman et al (J. Org.Chem. 1989, 54, 1442) to a carbamate form by the use of a chlorocarbonicester represented by the general formula (21) in the presence of a base.In the formula (21), R₈ stands for trichloroethyl or benzyl, the formerbeing preferred over the latter. The base to be used in the reaction ispossessed of steric hindrance large enough to avoid reacting with theacid chloride. The bases that are effectively usable herein are protonsponge and Hunig base, for example. The solvents that are favorablyusable herein include such halogenated hydrocarbons as methylenechloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane, forexample. Generally, 1,2-dichloroethane is desirably used. The reactiontemperature is practicable in the range of from -180° C. to 100° C.Generally, the reaction performed at temperatures in the range of from0° C. to normal room temperature yields satisfactory results. The secondstep resides in conversion of a carbamate form (22) into an epoxy formwith a peracid. Generally, the reaction using m-chloroperbenzoic acid asthe peracid yields fully satisfactory results. The solvents that arefavorably usable herein include such halogen type solvents as methylenechloride, chloroform, and carbon tetrachloride, for example. Generally,methylene chloride is used. The reaction temperature is practicable inthe range of from -80° C. to 50° C. Generally, the reaction carried outat temperatures in the range of from 0° C. to room temperature yieldssatisfactory results. The third step resides in converting the epoxyform (23) into a bridgehead-hydroxyl group form (24) through reducingring cleavage. As the reducing agent, such metal hydride compounds assodium borohydride and sodium cyanoborohydride are usable. The reactionperformed under the acidic conditions using acetic acid, hydrochloricacid, or methanesulfonic acid yields desirable results. Particularly,the reduction is desirably effected with sodium borohydride by the useof acetic acid both as solvent and acid catalist. The reactiontemperature is practicable in the range of from -80° C. to 50° C.Particularly, the reaction performed at temperatures in the range offrom 0° C. to room temperature yields satisfactory results. The fourthstep resides in producing a dihydroxyamine (25) by the simultaneousreduction of the carbamate moiety and acetate moiety of the hydroxyl(24) in the bridgehead portion. The reducing agents that are effectivelyusable for the reaction include lithium aluminum hydride, aluminumdiisobutyl hydride, and lithium borohydride, for example. Among otherreducing agents mentioned above, lithium aluminum hydride proves to beparticularly desirable. The solvents that are desirably usable hereininclude such ethers as ether, THF, DME, and dioxane, for example. Amongother solvents mentioned above, THF proves to be particularly desirable.The reaction temperature is practicable in the range of from -40° C. to100° C., preferably from 0° C. to room temperature. The fifth stepresides in converting the secondary hydroxyl group of a dihydroxyamineform (25) into a hydroxyketone form (26) through oxidation. Theoxidizing agents that are effectively usable in the conversion includechromic acid, potassium permanganate, DMSO-DCC, and DMSO-oxalylchloride, for example. Among other oxidizing agents, DMSO-oxalylchloride proves to be particularly desirable. The solvent to be usedherein may be a halogenous solvent such as dichloromethane orchloroform. Among other solvents usable at all herein, dichloromethaneproves to be particularly desirable. The reaction can be performed attemperatures in the range of from -100° C. to 0° C., preferably from-80° C. to -50° C. The sixth step for producing an indole form (27) andthe seventh step for producing a compound represented by the generalformula (27') having a hydrogen atom as R₂ can be carried out under thesame conditions as those shown respectively in the first step and thesecond step in Chart 1.

In the compounds of the general formula (1), those compounds that have ahydroxyl group as R₅ and alkyl of 2 to 5 carbon atoms, cycloalkylalkylof 3 to 6 carbon atoms, trans-alkenyl of 4 to 5 carbon atoms, allyl, orfuranyl-2-ylalkyl as R₁ can be produced through the following route(Chart 6). The first and second steps jointly reside in causing an8a-hydroxycarbamate form (24) obtained in consequence of the first,second, and third steps in Chart 5 to be converted into an amide form(29) via a secondary amine (28). These steps can be carried out inaccordance with the respective procedures of the second and third stepsof Chart 3. The third step resides in converting an amide acetate form(29) into a dihydroxyamine form (30). This step can be carried out bythe same procedure as that of the fourth step of Chart 5. The fourthstep, similarly to the fifth step of Chart 5, resides in oxidizing thesecondary hydroxyl group of the dihydroxyamine form (30) into a ketone.Further, the fifth step for producing an indole form (32) and the sixthstep for producing a compound represented by the general formula (32')having a hydrogen atom as R₂ can be produced under the same conditionsas those, respectively, of the first and second steps of Chart 1.##STR11##

The isoquinoline derivatives represented by the general formula (101)can be produced by following the procedure consisting of the followingsteps.

To be specific, a compound represented by the general formula (101) isobtained by reaction of a chlorocarbonic ester with an enaminerepresented by the general formula (102): ##STR12## [wherein R₁₀₂, R₁₀₃,R₁₀₄, R₁₀₅, and R₁₀₆ have the same meanings as defined above] in thepresence of a suitable base thereby forming a carbamate form representedby the general formula (103): ##STR13## [wherein R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅,R₁₀₆, and R₁₀₇ have the same meanings as defined above], epoxidizing theolefin moiety of the carbamate form, thereby giving rise to an epoxyform represented by the general formula (104): ##STR14## [wherein R₁₀₂,R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, and R₁₀₇ have the same meanings as definedabove], and then reducing the epoxy form under acidic conditions therebyobtaining a 4aα-aryl-8aβ-hydroxydecahydroisoquinoline represented by thegeneral formula (101a): ##STR15## [wherein R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆,and R₁₀₇ have the same meanings as defined above].

The production of the compound of this invention can be effected morespecifically under the following conditions. Of the compounds of thegeneral formula (101b), those compounds that have a methoxy group asR₁₀₆ are produced specifically under the following conditions (Chart101). ##STR16##

The first step resides in conversion of the methyl group on the nitrogenatom of an enamine form (102)' synthesizable in accordance with themethod reported by Zimmerman et al [J. Org. Chem., 541442 (1989)] to acarbamate form (103)' by the use of a chlorocarbonic ester in thepresence of a base. The bases that are effectively usable in theconversion include tertiary amines such as triethylamine,diisopropylethylamine, and proton sponge, and pyridine, and imidazole,for example. Among other bases cited above, proton sponge anddiisopropylethylamine which are tertiary amines having steric hindranceare enough to avoid reacting with an acid chloride are particularlydesirable. The solvents that are effectively usable herein are thoughtto include halogenous solvents such as methylene chloride, chloroform,carbon tetrachloride, and 1,2-dichloroethane and ethers such as THF,DME, and dioxane, for example. Generally, halogenous solvents,especially 1,2-dichloroethane, are favorably usable. The reactiontemperature is practicable in the range of from -80° C. to 100° C.Generally, the reaction performed at temperatures in the range of from0° C. to room temperature yields satisfactory results.

The second step resides in converting a carbamate form (103)' into anepoxy form. As regards the epoxidizing agent, all the reacting agentsthat are generally used for epoxidation are thought to be usable. Amongother conceivable epoxidation agents, peracids such as perbenzoic acid,m-chloroperbenzoic acid, peracetic acid, and trifluoroperacetic acid andhydrogen peroxide are favorably used. Particularly, m-chloroperbenzoicacid proves to be desirable. The solvents that are effectively usableherein are thought to include halogenous solvents such as methylenechloride, chloroform, and carbon tetrachloride and aromatic hydrocarbontype solvents such as benzene and toluene, for example. Generally,halogenous solvents, especially methylene chloride, are favorably used.The reaction temperature is practicable in the range of from -80° C. to50° C. Generally, the reaction carried out at temperature in the rangeof from 0° C. to room temperature yields satisfactory results.

The third resides in converting an epoxy form (104)' into a bridgeheadhydroxyl group form (101a)' by reductive ring cleavage. As regards thereducing agent for this conversion, all the reducing agents that aregenerally used for reduction of an epoxy group are through to be usable.The reducing agents that are inactive to the carbamate moiety and theacetate moiety and capable of selectively reducing the epoxy group suchas, for example, metal hydride compounds like sodium borohydride, sodiumcyanoborohydride, and zinc borohydride are favorably usable. In thiscase, the reaction yields desirable results when the solution usedtherefor is adjusted for acidity in advance of use. The acids that areeffectively usable for this adjustment are thought to include inorganicacids such as hydrochloric acid, sulfuric acid, nitric acid, andphosphoric acid, and organic acids such as acetic acid, propionic acid,oxalic acid, methanesulfonic acid, benzenesulfonic acid, andtoluenesulfonic acid, for example. The solvents that are effectivelyusable herein are thought to include ethers such as THF, ether, and DME,halogenous solvents such as methylene chloride and chloroform, alcoholssuch as methanol and ethanol, and organic acids such as acetic acid,propionic acid, and butanoic acid, which are usable as solvents, forexample. The reduction, with sodium borohydride in acetic acid both assolvent and acid catalyst, yields desirable results. The reactiontemperature is practicable in the range of from -80° C. to 50° C. Thereaction carried out at temperatures in the range of from 0° C. to roomtemperature yields satisfactory results.

The fourth step resides in producing a dihydroxyamine form (101d) bysimultaneous reduction of the carbamate moiety and the acetate moiety ofthe bridgehead hydroxyl group form (101a)'. As regards the reducingagent, all the metal hydrides that the generally used as a reducingagent are though to be favorably usable. Such metal hydride compounds aslithium aluminum hydride, diisobutyl aluminum hydride, aluminum hydride,lithium borohydride, and diborane, which are possessed of strongreducing potential, may be cited as examples. Among other reducingagents mentioned above, lithium aluminum hydride provides to beparticularly desirable. As regards the solvent, where lithium aluminumhydride, lithium borohydride, or diborane is used as a reducing agent,such ethers as ether, THF, DME, and dioxane are favorably used. Amongother solvents cited above, THF proves to be particularly desirable.Where diisobutyl aluminum hydride or aluminum hydride is sued as areducing agent, such aromatic type hydrocarbons as benzene and tolueneare favorably used as solvents. The reaction can be effected attemperatures in the range of from -40° C. to 100° C., preferably from 0°C. to normal room temperature.

The fifth step resides in converting the secondary hydroxyl group of thedihydroxyamine form (101d) into the hydroxyketone form (101b)' byoxidation. As regards the oxidizing agent, all the compounds that aregenerally used for the oxidation of a secondary hydroxyl group arethrough to be usable. Specifically, chromic acid type oxidizing agents,permanganic acid type oxidizing agents, DMSO-DCC type oxidizing agents,and DMSO-oxalyl chloride type oxidizing agents may be cited as examples.The DMSO-oxalyl chloride type oxidizing agents are favorably used. Asregards the solvent, such halogenous solvents as dichloromethane andchloroform, such ethers as ether, THF, and DME, and such aprotic dipolarsolvents as DMSO and DMF are thought to be effectively usable. Thehalogenous solvents, particularly dichloromethane, prove to beparticularly desirable. The reaction can be carried out at temperaturesin the range of from -100° C. to 50° C. In the case of the DMSO-oxalylchloride type oxidizing agents, the reaction carried out at temperaturesin the range of from -80° C. to -50° C. yields desirable results.

The compounds of the general formula (101b)" having a substituent otherthan methyl as R₁ can be produced by using the following conditions(Chart 102). ##STR17##

The first step resides in causing an 8aβ-hydroxycarbamate form (101a)'formed in consequence of the first, second, and third steps of Chart 1to be converted into a secondary amine (101e)' by deprotection ofprotective group on the nitrogen atom. Where R₁₀₇ is2,2,2-trichloroethyl, this step can be effected by the reduction withzinc in the presence of an acid catalyst. The acids that are effectivelyusable for the catalysis are thought to include inorganic acids such ashydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid andorganic acids such as acetic acid, propionic acid, oxalic acid,methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid,for example. As regards the solvent, alcohols such as methanol andethanol, ethers such as ether, THF, and DME, aprotic dipolar solventssuch as DMSO and DMF, and such organic acids as acetic acid, propionicacid, and butanoic acid, which are usable as solvents may be cited asexamples. Generally, the reaction using acetic acid both as catalyst andsolvent yields desirable results. The reaction temperature isconceivable in the range of from -20° C. to 150° C., preferably from 0°C. to 50° C. Where R₁₀₇ is benzyl, the removal of the protective groupcan be attained under hydrolyzing conditions. As regards the catalyst,all the compounds generally used for hydrolysis are thought to beeffectively usable. Among other catalysts available palladium/carbon andplatinum catalyst are favorably used. The hydrogen pressure isconceivable in the range of from 1 to some tens of atmospheres.Generally, the reaction performed under 1 atmosphere yields fullysatisfactory results. As regards the solvent for use in the reaction,alcoholic solvents such as methanol and ethanol, etherial solvents suchas THF and DME, and aromatic hydrocarbon type solvents such as benzeneand toluene are thought to be effectively usable.

The second step resides in producing an amide form (101f)' by thereaction of a secondary amine (101e)' with an acid chloride or acidanhydride in the presence of a base. The base than is effectively usablefor this reaction include tertiary amines such as triethylamine,diisopropylethylamine, and proton sponge and pyridine,dimethylaminiopyridine, and imidazole, for example. In the reactionperformed in the presence of an acid chloride, the use of triethylamineor protone sponge as the base brings about fully satisfactory results.The solvents that are effectively usable in the reaction includehalogenous solvents such as methylene chloride, chloroform, carbontetrachloride, and 1,2-dichloroethane, ethers such as ether, THF, andDME, and pyridine, for example. Particularly in the reaction that isperformed in the presence of an acid chloride, halogenous solvents aredesirably used and methylene chloride is particularly favorably. In thereaction carried out in the presence of an acid anhydride, pyridine isused desirably both as base and solvent. The reaction is practicable attemperatures in the range of from -80° C. to 100° C. Particularly, thereaction performed at temperatures in the range of from 0° C. to roomtemperature.

The subsequent third step resides in converting an amide acetate form(101f)' to a dihydroxyamine form (101g)'. This step can be executed byfollowing the procedure of the fourth step of Chart 1. The fourth step,similarly to the fifth step of Chart 1, resides in oxidizing a secondaryhydroxyl group form (101g)' into a ketone form (101b)".

Further, the compounds (101a)" having a 2,2,2-trichloroethoxycarbonyl asR₁₀₁ and a hydrogen atom as R₁₀₂, R₁₀₃, R₁₀₄, and R₁₀₅ and the compounds(101g)' having R₁₀₈ CH₂ as R₁₀₁ and a hydrogen atom as R₁₀₂, R₁₀₃, R₁₀₄,and R₁₀₅ can be produced from an N-methylenamine form (102)' obtained bythe method reported by Evans et al. [D. A. Evans et al., J. Am. Chem.Soc., 102, 5955, (1980)] through the procedure consisting of the firstsecond, and third steps of chart 1 and the first, second, and thirdsteps of Chart 102 as illustrated in Chart 103. By the same procedure,the compounds having varying substituents as R₁₀₂, R₁₀₃, R₁₀₄, and R₁₀₅can be produced. ##STR18##

The indole derivatives of the aforementioned general formula (1) can beobtained by using the isoquinoline derivatives of this invention asintermediates for synthesis.

Since the compounds of the present invention are antagonists possessedof very high selectively for delta receptors, they become highly usefulprobes in the study of complicated opioid receptors (consisting of thethree subtypes, μ, δ, and κ).

The opioid receptors have some bearing on complicated actions such asgastrointenstinal tract transportation, renal function, appetite,memory, secretion of gastric juice, analgesia, circulatory function,respiration, and psychiatric action. Thus, the elucidation of detailedpharmacological actions of the subtypes is desired. The compounds ofthis invention, which are possessed of very high selectively for thedelta-receptors are expected to play a role in this elucidation.Further, the delta-opioid receptors relate to analgasia, immunity, andcirculatory functions (particularly blood pressure). The ligands, whichare highly selective for these receptors have the possibility of beingutilized as such medicines as analgesics, immunorepressants [usable intransplantation of internal organs (kidney, liver, and heart), skintransplantations, and autoimmune diseases (sparingly tractable diseasessuch as rheumatism, various allergies, collagen disease, andoesteoporosis)], and antihypertensive agents. Since the compounds ofthis invention possesses selective δ-receptor antagonist, in particular,they are expected to serve as an outstanding immunorepressant amongother diseases mentioned above.

When a compound of this invention is used clinically as animmunorepressive agent, it may be in the form of a free base or a saltthereof and may be suitably mixed with excipients such as stabilizers,buffers, diluents, isotonizers, and antiseptics. As regards the dosageform, the immunorepressive agent may be in injection, form capsules,suppository, or oral pills. The dosage is suitably determined by thesubject of administration, the method of administration, and thesymptom. When the medicine is used in the form of injection, the dailydose is selected in the range of from 0.0001 to 1 g. When it isadministered orally, the daily dose is in the range of from 0.001 to 10g. In a medicine using the compound of this invention, the propercontent of this compound is thought to be in the range of from 0.05 to99%. Generally, the content of this compound in injection form is in therange of from 0.5 to 20% and in pill form in the range of from 0.1 to50%.

EXAMPLES

Now, the present invention will be described more specifically belowwith the reference to working examples. It should be noted, however,that this invention is not limited by these examples.

EXAMPLE 12-Methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline1 ##STR19##

A solution of 161 mg of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 0.064 ml of phenyl hydrazine in 3 ml of ethanol was refluxed. Thesolution so refluxed and 0.383 ml of methanesulfonic acid added theretomeanwhile was stirred and continuously refluxed for one hour. Theresultant reaction mixture was cooled to room temperature and 10 ml of asaturated aqueous solution of sodium hydrogen carbonate was addedthereto and cooled with ice. The produced mixture was extracted threetimes from 10 ml of chloroform. The organic layers consequentlyseparated were combined, washed with 5 ml of a saturated aqueous salinesolution, dried, and concentrated, to obtain 250 mg of a powder. Thispowder, when it was separated and refined by column chromatography[silica gel:methanol:chloroform:28% aquaammonia=2.5:97.5:0.1-5.0:95.0:0.1], produced 150 mg of the captionedcompound (yield 73.5%).

IR (KBr) cm⁻¹ : 3400, 2936, 1609, 1448

NMR (CDCl₃) 500 MHz δ: 1.98 (1H, m), 2.10 (1H, m), 2.32 (3H, s), 2.39(1H, m), 2.58 (1H, m), 2.65 (1H, t, J=11.6 Hz), 2.73 (1H, d, J=12.2 Hz),2.87-3.06 (4H, m), 3.07 (1H, d, J=15.9 Hz), 3.67 (3H, s), 6.61 (1H, m),7.01-7.10 (5H, m), 7.20 (1H, m), 7.43 (1H, m), 7.65 (1H, brs)

Mass (m/e): 346 (M⁺)

Similarly,2-methyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using 4-nitrophenylhydrazine instead of phenylhydrazine,2-methyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and2-methyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare obtained by using 3-nitrophenylhydrazine instead, and2-methyl-4aα-(3-methyoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using 2-nitrophenylhydrazine instead.

EXAMPLE 22-Methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-isoquinoline2 ##STR20##

In an atmosphere of argon, 95.7 mg of2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand 93.1 mg of potassium-t-butoxide were dissolved in 3 ml of anhydrousDMF and the resultant solution and 0.08 ml of 1-propane thiol addedthereto were stirred at 140° C. for 7.5 hours. The produced mixture and10 ml of a saturated aqueous solution of sodium hydrogen carbonate addedthereto was extracted three times from 30 ml of a chloroform:methanol(5:1) mixed solvent. The organic layers consequently separated werecombined, washed with 5 ml of a saturated saline solution, dried, andconcentrated, to afford 100 mg of a powder. This powder was suspended in1 ml of methanol and converted by the addition of methanesulfonic acidinto a methanesulfonate. When the methanesulfonate was separated andrefined by column chromatography [Sephadex LH-20: methanol], it produced51.6 mg of the methanesulfonate of the captioned compound (yield 43.5%).

IR (KBr) cm⁻¹ : 3400, 1586, 1466

NMR (CDCl₃) 500 MHz δ: 2.00 (1H, m), 2.31 (3H, s), 2.44-264 (3H, m),2.81 (3H, s), 2.81-2.90 (2H, m), 2.97 (1H, m), 3.10 (1H, d, J=16.5 Hz),3.36-3.44 (2H, m), 3.61 (1H, m), 6.53 (1H, m), 6.90-6.99 (4H, m), 7.04(1H, t, J=7.9 Hz), 7.18 (1H, d, J=7.9 Hz), 7.34 (1H, d, J=7.3 Hz), 9.24(1H, s), 9.53 (1H, brs), 10.46 (1H, s)

Mass (FAB): 333 (M⁺ +1)

Elementary analyses:

    ______________________________________                                        For C.sub.22 H.sub.24 N.sub.2 O.CH.sub.3 SO.sub.3 H                                     C    H           N      S                                           ______________________________________                                        Calculated  64.46  6.59        6.54 7.48                                      Found       64.12  6.31        6.25 7.33                                      ______________________________________                                    

Similarly,2-methyl-4aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-[2,3-g]isoquinolineinstead, and2-methyl-4aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using 2-methyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead.

EXAMPLE 32-Methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline3 ##STR21##

A solution of 250 mg of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 260 mg of p-tollyl hydrazine hydrochloride in 3 ml of ethanol wasrefluxed. The solution thus refluxed and 0.58 ml of methanesulfonic acidadded meantime thereto was stirred and continuously refluxed for onehour. The resultant mixture was cooled to room temperature. The cooledreaction mixture and 10 ml of a saturated aqueous solution of sodiumhydrogen carbonate added thereto and cooled with ice was extracted threetimes from 10 ml of chloroform. This organic layers consequentlyseparated were combined, washed with a saturated aqueous salinesolution, dried, and concentrated, to obtain 400 mg of a powder. Whenthis powder was separated and refined by column chromatography [silicagel:methanol:chloroform:aqueous 28% ammoniasolution=2.5:97.5":0.1-5.0":9.50:0.1], it produced 313 mg of thecaptioned compound (yield 94.9%).

IR (KRr) cm⁻¹ : 3402, 2922, 1607, 1580

NMR (CDCl₃) 500 MHz δ: 2.12 (1H, m), 2.25 (1H, m), 2.40 (1H, m), 2.42(3H, s), 2.43 (3H, s), 2.60 (1H, m), 2.71-2.79 (2H, m), 2.86-2.91 (3H,m), 3.03-3.08 (2H, m), 3.68 (3H, s), 6.62 (1H, m), 6.90 (1H, d, J=8.6Hz), 6.97-6.98 (2H, m), 7.10 (2H, dd, J=18.3 Hz, 7.9 Hz), 7.18 (1H, s),7.81 (1H, s)

Mass (m/e): 360 (M⁺)

Similarly,2-methyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-isoquinolineis produced by using o-tollyl hydrazine hydrochloride instead ofp-tollylphenylhydrazine.

EXAMPLE 42-Methyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline4 ##STR22##

In an atmosphere of argon, 237 mg of2-methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand 333 mg of potassium-t-butoxide were dissolved in 8 ml of anhydrousDMF and 0.28 ml of 1-propane thiol was added thereto. The resultantmixture was stirred at 140° C. for 4.5 hours and then cooled to roomtemperature. The mixture was distilled under a vacuum to expel DMF. Thedistillate and 10 ml of a saturated aqueous solution of sodium hydrogencarbonate added thereto were extracted three times from 30 ml of achloroform:methanol (5:1) mixed solvent. The organic layers consequentlyseparated were combined, washed with a saturated aqueous salinesolution, dried, and concentrated, to obtain 166 mg of a powder. Thispowder was suspended in 1 ml of methanol and converted by the additionof methanesulfonic acid into a methanesulfonate. When thismethanesulfonate was refined by column chromatography [Sephadex, LH-20;methanol], it produced 134 mg of the methanesulfonate of the captionedcompound (yield 46.1%).

IR (KBr) cm⁻¹ : 3400, 2936, 2732, 1599

NMR (DMSO-d₆) 500 MHz δ: 2.00 (1H, s), 2.33 (3H, s), 2.37 (3H, s),2.51-2.64 (3H, m), 2.81 (3H, s), 2.80-2.97 (3H, m), 3.06 (1H, d, J=16.5Hz), 6.53 (1H, d, J=7.9 Hz), 6.80 (1H, d, J=8.6 Hz), 6.88 (1H, s), 6.92(1H, d, J=7.9 Hz), 7.03 (1H, t, J=7.9 Hz), 7.06 (1H, d, J=8.6 Hz), 7.12(1H, s), 9.24 (1H, s), 9.53 (1H, brs), 10.46 (1H, s)

Mass (FAB): 347 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.23 H.sub.26 N.sub.2 O.CH.sub.3 SO.sub.3 H.0.1H.sub.2 O                        C    H           N      S                                           ______________________________________                                        Calculated  64.87  6.85        6.30 7.22                                      Found       64.62  7.04        6.16 7.53                                      ______________________________________                                    

Similarly,2-methyl-4aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline.

EXAMPLE 52-Methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline5 ##STR23##

A solution of 250 mg of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 180 mg of 4-chlorophenylhydrazine in 3 ml of ethanol was refluxed.The solution thus was refluxed and 0.6 ml of methanesulfonic acid addedmeantime thereto were stirred and continuously refluxed for one hour.The resultant reaction mixture was cooled to room temperature. Thecooled reaction mixture and 10 ml of a saturated aqueous solution ofsodium hydrogen carbonate added thereto and cooled with ice andextracted three times from 10 ml of chloroform. The organic layersconsequently separated were combined, washed with a saturated aqueoussaline solution, dried, and concentrated, to afford 420 mg of a powder.When this powder was separated and refined by column chromatography[silica gel:methanol:chloroform:28% aquaammonia=2.5:97.5:0.1-5.0:95.0:0.1], it produced 315 mg of the captionedcompound (yield 90.4%).

IR (KBr) cm⁻¹ : 3418, 2936, 1582, 1446

NMR (CDCl₃) 500 MHz δ: 2.09 (1H, m), 2.23 (1H, m), 2.40 (1H, m), 2.43(3H, s), 2.51-2.02 (2H, m), 2.76 (1H, t, J=11.6 Hz), 2.82-2.91 (3H, m),3.02 (1H, m), 3.09 (1H, d, J=15.3 Hz), 3.68 (3H, s), 6.63 (1H, dd, J=7.9Hz, 2.4 Hz), 6.95 (2H, m), 7.02 (1H, dd, J=8.5 Hz, 1.8 Hz), 7.10 (1H, t,J=7.9 Hz), 7.15 (1H, d, J=7.9 Hz), 7.33 (1H, d, J=1.8 Hz), 8.13 (1H,brs)

Mass (m/e): 380 (M⁺)

Similarly,2-methyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-methyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare obtained by using 3-chlorophenylhydrazine instead of4-chlorophenylhydrazine and2-methyl-4aα-(3-methoxyphenyl)-7chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using 2-chlorophenylhydrazine instead.

EXAMPLE 62-Methyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline4 ##STR24##

In an atmosphere of argon, 255 mg of2-methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand 452 mg of potassium-t-butoxide were dissolved in 6 ml of DMF and theresultant solution and 0.4 ml of 1-propane thiol added thereto werestirred at 140° C. for 5.5 hours. The resultant reaction mixture wascooled to room temperature, distilled under a vacuum to expel DMF,combined with 5 ml of a saturated aqueous solution of sodium hydrogencarbonate, and extracted three times from 30 ml of chloroform. Theorganic layers consequently separated were combined, washed with asaturated aqueous saline solution, dried, and concentrated, to afford278 mg of a powder. When this powder was suspended in 1 ml of methanol,converted by the addition of methanesulfonic acid into amethanesulfonate, and separated and refined by column chromatography[Sephadex, LH-20; methanol], there were obtained 100 mg of themethanesulfonate of the captioned compound (yield 41.2%).

IR (KBr) cm⁻¹ : 3240, 1601, 1586, 1450

NMR (DMSO-d₆) 500 MHz δ: 2.07 (1H, t, J=12.8 Hz), 2.32 (3H, s), 2.53(1H, m), 2.64 (2H, m), 2.79 (3H, s) 2.84-2.97 (3H, m), 3.09 (1H, d,J=15.9 Hz), 3.35 (2H, m), 3.58 (1H, d, J=11.0 Hz), 6.54 (1H, dd, J=7.9Hz, 1.8 Hz), 6.90 (2H, m), 6.97 (1H, dd, J= 8.6 Hz, 1.8 Hz), 7.04 (1H,t, J=7.9 Hz), 7.20 (1H, d, J=8.6 Hz), 7.37 (1H, d, J=1.9 Hz), 9.28 (1H,s), 10.03 (1H, brs), 10.86 (1H, s)

Mass (FAB): 367 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.22 H.sub.23 N.sub.2 OCl.CH.sub.3 SO.sub.3 H                                 C       H      N         Cl   S                                       ______________________________________                                        Calculated                                                                              59.67     5.88   6.05    7.66 6.93                                  Found     59.78     5.93   6.24    7.45 6.63                                  ______________________________________                                    

Similarly,2-methyl-4aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-methyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-methyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 72-Methyl-4aα-(3methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline7 ##STR25##

A solution of 250 mg of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 164 mg of hydrochloride-2-fluorophenylhydrazine in 3 ml of ethanolwas refluxed. The solution thus refluxed and 0.6 ml of methanesulfonicacid added meantime thereto were stirred and continuously refluxed forone hour. The resultant reaction mixture was cooled to normal roomtemperature. The cooled reaction mixture and 10 ml of a saturatedaqueous solution of sodium hydrogen carbonated added thereto and cooledwith ice were extracted three times from 10 ml of chloroform. Theorganic layers consequently separated were combined, washed with 5 ml ofa saturated aqueous saline solution, dried, and concentrated, to obtain407 mg of a powder. When this powder was separated and refined by columnchromatography [silica gel:methanol:chloroform:28% aquaammonia=2.5:97.5:0.1-5.0:95.0:0.1], it produced 120 mg of the captionedcompound (yield 36.1%).

IR (KBr) cm⁻¹ : 3412, 2938, 1607, 1491

NMR (CDCl₃) 500 MHz δ: 2.10 (1H, m), 2.20 (1H, m), 2.41 (3H, s), 2.43(1H, s), 2.60 (1H, m), 2.76 (1H, t, J=11.6 Hz), 2.81-2.98 (4H, m), 3.05(1H, m), 3.13 (1H, m), 3.69 (3H, s), 6.64 (1H, m), 6.79 (1H, m), 6.96(3H, m), 7.11 (1H, t, J=7.9 Hz), 7.17 (1H, d, J=7.9 Hz), 8.04 (1H, brs)

Mass (m/e): 364 (M⁺)

Similarly,2-methyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and2-methyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβoctahydro-6H-indolo[2,3-g]isoquinolineare obtained by using 3-fluorophenylhydrazine instead of2-fluorophenyl-hydrazine, and2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using 4-fluorophenylhydrazine instead.

EXAMPLE 82-Methyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline8 ##STR26##

In an atmosphere of argon, 136 mg of2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand 126 mg of potassium-t-butoxide were dissolved in 3 ml of anhydrousDMF and the resultant solution and 0.1 ml of 1-propane thiol addedthereto were stirred at 140° C. for three hours. The resultant reactionmixture was cooled to room temperature, distilled under a vacuum toexpel DMF, combined with a saturated aqueous solution of sodium hydrogencarbonate, and extracted three times from 30 ml of chloroform. Theorganic layers consequently separated were combined, washed with asaturated aqueous saline solution dried, and concentrated, to afford 268mg of a powder. This powder was separated and refined by columnchromatography [silica gel:methanol:chloroform:28% aquaammonia=5:95:0.1-10:90:0.1]. The powder was suspended in 1 ml ofmethanol and converted by the addition of methanesulfonic acid into amethanesulfonate. When the methanesulfonate was refined by Sephadexcolumn (LH-20:methanol), there was obtained 38.7 mg of themethanesulfonate of the captioned compound (yield 23.1%).

IR (KBr) cm⁻¹ : 3400, 1599, 1400

NMR (DMSO-d₆) 500 MHz δ: 2.01 (1H, m), 2.32 (3H, s), 2.46-2.57 (3H, m),2.82 (3H, s), 2.89 (2H, m), 2.97 (1H, m), 3.10 (1H, m), 3.35 (2H, M),3.62 (1H, d, J=11.6 Hz), 6.55 (1H, m), 6.80 (1H, m), 6.89-6.99 (3H, m),7.04 (1H, m), 7.18 (1H, m), 9.27 (1H, s), 9.54 (1H, brs), 11.09 (1H, s)

Mass (FAB) 351 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.22 H.sub.23 N.sub.2 OF.CH.sub.3 SO.sub.3 H                                    C    H           N      S                                           ______________________________________                                        Calculated  61.86  6.09        6.27 7.18                                      Found       61.77  6.12        6.35 7.43                                      ______________________________________                                    

Similarly,2-methyl-4aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl)-7fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-methyl-4aα-(3-hydroxyphenyl-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-[2,3-g]isoquinolineinstead.

EXAMPLE 92-Methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline9 ##STR27##

A solution of 250 mg of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 225 mg of p-bromophenylhydrazine hydrochloride in 3 ml of ethanolwas refluxed. The solution thus refluxed and 0.594 ml of methanesulfonicacid added meantime thereto were stirred and continuously refluxed forone hour. The resultant reaction mixture was cooled to room temperature.The cooled reaction mixture and 10 ml of a saturated aqueous solution ofsodium hydrogen carbonate added thereto and cooled with ice wereextracted three times from 10 ml of chloroform. The organic layersconsequently separated were combined, washed with 5 ml of a saturatedaqueous saline solution, dried, and concentrated, to afford 474 mg of apowder. When this powder was separated and refined by columnchromatography [silica gel:methanol:chloroform:28% aquaammonia=2.5:97.5:0.1-5.0:95.0:0.1], it produced 348 mg of the captionedcompound (yield 89.5%).

IR (KBr) cm⁻¹ : 3412, 2938, 1580, 1466, 1446

NMR (CDCl₃) 500 MHz δ: 2.09 (1H, m), 2.23 (1H, m), 2.39 (1H, s), 2.43(3H, s), 2.50-2.53 (2H, m), 2.73-2.89 (4H, m), 3.01 (1H, m), 3.09 (1H,d, J=15.3 Hz), 3.68 (3H, s), 6.63 (1H, dd, J=7.9 Hz, J=1.8 Hz),6.93-6.95 (2H, m), 7.09-7.16 (3H, m), 7.49 (1H, d, J=1.8 Hz), 8.21 (1H,brs)

Mass (m/e): 424 (M⁺)

Similarly,2-methyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-methyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβoctahydro-6H-indolo[2,3-g]isoquinolineare obtained by using 3-bromophenylhydrazine instead of4-bromophenylhydrazine, and2-methyl-4-aα-(3-methoxyphenyl)-7-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using 2-bromophenylhydrazine instead.

EXAMPLE 102-Methyl-4aα-(3hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline10 ##STR28##

In an atmosphere of argon, 248.5 mg of2-methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand 296 mg of potassium-6-butoxide were dissolved in 5 ml of anhydrousDMF and the resultant solution and 0.248 ml of 1-propane thiol addedthereto were stirred at 140° C. for 5.5 hours. The resultant reactionmixture was cooled to room temperature, distilled under a vacuum toexpel DMF, combined with 10 ml of a saturated aqueous solution of sodiumhydrogen carbonate, and extracted the times from 20 ml of achloroform:methanol mixed solvent. The organic layers consequentlyseparated are combined, washed with 10 ml of a saturated aqueous salinesolution, dried, and concentrated, to afford 208 mg of a powder. Thispowder was suspended in 1 ml of methanol, converted by addition ofmethanesulfonic acid into a methanesulfonate, and separated and refinedby column chromatography [Sephadex LH-20; methanol], to afford 96 mg ofthe methansulfonate of the captioned compound (yield 32.4%).

IR (KBr) cm⁻¹ : 3390, 1584, 1468

NMR (DMSO-d₆) 500 MHz δ: 2.00 (1H, m), 2.33 (3H, s), 2.54-2.68 (3H, m),2.82 (3H, d, J=4.9 Hz), 2.84-2.98 (3H, m), 3.09 (1H, d, J=15.9 Hz),3.33-3.44 (2H, m), 3.61 (1H, d, J=12.2 Hz), 6.54 (1H, dd, J=7.9 Hz,J=1.8 Hz), 6.87 (1H, s), 6.91 (1H, d, J=7.9 Hz), 7.04 (1H, t, J=7.9 Hz),7.08 (1H, dd, J=8.5 Hz, J=1.8 Hz), 7.16 (1H, d, J=8.6 Hz), 7.52 (1H, d,J=1.8 Hz), 9.26 (1H, s), 9.51 (1H, brs), 10.87 (1H, s)

Mass (FAB 411 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.22 H.sub.23 N.sub.2 OBr.CH.sub.3 SO.sub.3 H                                 C       H      N         Br   S                                       ______________________________________                                        Calculated                                                                              54.44     5.36   5.52    15.75                                                                              6.32                                  Found     54.24     5.58   5.37    15.35                                                                              6.61                                  ______________________________________                                    

Similarly,2-methyl-4aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-methyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis obtained by using 2-methyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead.

EXAMPLE 112Methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβoctahydro-6-methyl-indolo[2,3-g]isoquinoline11 ##STR29##

In an atmosphere of argon, 35 mg of sodium hydroxide (60% mineral oildispersion) was washed with 2 ml of anhydrous THF and suspended in 2 mlof anhydrous hexamethylphosphoramide (HMPA). In the resultantsuspension, a solution of 138 mg of2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinein 3 ml of anhydrous HMPA added dropwise thereto was stirred at roomtemperature for five hours. The resultant reaction mixture and asolution of 0.2 ml of methyl iodide in 4.8 ml of anhydrous HMPA addeddropwise thereto was stirred at room temperature for 16 hours. Theproduced reaction solution was combined with 5 ml of water and extractedtwo times from 10 ml of ethyl acetate. The organic layers consequentlyseparated were combined, washed with a saturated aqueous salinesolution, dried, and concentrated, to afford 1.85 g of an oil substance.When this only substance was separated and refined by columnchromatography [silica gel:methanol:chloroform:28% aquaammonia=2.5:97.5:0.1-5.0:95.0:0.1] , it produced 125 mg of the captionedcompound (yield 87.0%).

IR (liquid film method) cm⁻¹ : 2938, 1607, 1580, 1470

NMR (CDCl₃) 500 MHz δ: 2.23 (1H, m), 2.33 (1H, m), 2.47 (3H, s), 2.50(1H, s), 2.74-2.87 (3H, m), 2.95-3.02 (3H, m), 3.14-3.17 (2H, m), 3.51(3H, s), 3.69 (3H, s), 6.65 (1H, m), 7.01-7.07 (3H, m), 7.11 (2H, m),7.19 (1H, d, J=7.9 Hz), 7.44 (1H, d, J=7.9 Hz)

Mass (m/e): 360 (M⁺)

Similarly,2-methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using 2-methyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using 2-methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-methyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline is obtained by using2-methyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinolineinstead. Similarly again,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 12 2-Methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline 12##STR30##

In an atmosphere of argon 118 mg of2methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineand 110 mg of potassium-t-tutoxide were dissolved in 2ml of anhydrousDMF and 0.1 ml of 1-propane thiol was added thereto. The producedmixture was stirred at 140° C. for 3.5 hours and then cooled to roomtemperature. The cooled mixture was distilled under a vacuum to expelDMF. The distillate and 10 ml of a saturated aqueous solution of sodiumhydrogen carbonate added thereto were extracted two times from 20 ml ofchloroform. The organic layers consequently separated were combined,washed with a saturated aqueous saline solution, dried, andconcentrated, to afford 120 mg of a powder. This powder was suspended in1 ml of methanol, converted by addition of methanesulfonic acid into amethanesulfonate, and thereafter refined by column chromatography[Sephadex LH-20; methanol], to produce 97.5 mg of the methanesulfonateof the captioned compound (yield 67.7%).

IR (KBr) cm⁻¹ : 3386, 2936, 2718, 1601

NMR (DMSO d₆) 500 MHz δ: 2.06 (1H, m), 2.32 (3H, m), 2.54-2.57 (2H, m),2,65 (1H, m), 2,83 (3H, s), 2.85 (1H, m), 2.90 (1H, m), 3.00 (1H, m),3,27-3.41 (3H, m), 3.52 (3H, s), 3.63 (1H, m), 6.55 (1H, dd, J=7.9 Hz,J=1.8 Hz), 6.94-6.99 (3H, m), 7.04-7.07 (2H, m), 7.30 (1H, d, J=8.6 Hz),7.37 (1H, d, J=7.3 Hz), 9.28 (1H, s), 9.53 (1H, brs)

Mass (FAB): 347 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.23 H.sub.26 N.sub.2 O.CH.sub.3 SO.sub.3 H.0.5H.sub.2 O                        C    H           N      S                                           ______________________________________                                        Calculated  63.83  6.92        6.20 7.10                                      Found       63.87  7.05        6.61 7.40                                      ______________________________________                                    

Similarly,2-methyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using 2-methyl-4aα-(3-methylphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphehyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline is obtained by using2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-methyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead. Similarly again,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydryxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline instead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-3methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis obtained by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 132-Methyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline13a and2methyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline13b ##STR31##

A solution of 250 mg of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 160 mg of M-tolyl hydrazine hydrochloride in 3 ml of ethanol wasrefluxed. The solution thus refluxed and 0.594 ml of methanesulfonicacid added meantime thereto were stirred and continuously refluxed forone hour. The resultant reaction mixture was cooled to room temperature.The cooled reaction mixture and 10 ml of a saturated aqueous solution ofsodium hydrogen carbonate added thereto and cooled with ice wereextracted three times from 10 ml of chloroform. The organic layersconsequently separated were combined, washed with 5 ml of a saturatedaqueous saline solution, dried, and concentrated, to afford 365 mg of anoily substance. This only substance was separated and refined by columnchromatography [silica gel:methanol:chloroform:28% aquaammonia=2.5:97.5:0.1-5.0:95.0:0.1], it produced 313 mg of a mixture ofthe captioned compounds (yield 94.9%).

IR (KBr) cm⁻¹ : 3390, 2898, 1607, 1580, 1462

NMR (CDCl₃) 500 MHz δ: 1.98 (1H, m), 2,09 (1H, m), 2.32 (3H, sX2), 2.38(1H, m), 2.40 (3H, sX2), 2.53-2.65 (3H, m), 2.73 (1H, m), 2.85-2.96 (3H,m), 3.03 (1H, m), 3.68 (3H, s), 6.61 (1H, m), 6.91 (1H, m), 6.99-7.10(4H, m), 7.31 (1H, m), 7.47 (1H, brsX2).

Mass (m/e): 360 (M⁺)

EXAMPLE 142-Methyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline14a and2methyl-4aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline14b ##STR32##

In an atmosphere of argon, 255.3 mg of a mixture of2-methyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-methyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand 477 mg of potassium t-butoxide were dissolved in 6 ml of anhydrousDMF. The resultant solution and 0.4 ml of 1-propane thiol added theretowere stirred at 140° C. for 3.5 hours.

The produced mixture was cooled at room temperature, distilled to expelDMF, combined with 10 ml of a saturated aqueous solution of sodiumhydrogen carbonate, and extracted three times from 20 ml of a mixedsolvent of chloroform:methanol=5:1. The organic layers consequentlyseparated were combined, washed with 10 ml of a saturated salinesolution, dried, and concentrated, to obtain 401 mg of a powder. Thispowder was suspended in 1 ml of methanol, converted by the addition ofmethanesulfonic acid into a methanesulfonate, and then separated andrefined by column chromatography [Sephadex LH-20; methanol], to produce58 mg of a mixture of methanesulfonates of the captioned compounds(yield 18.5%).

IR (KBr) cm⁻¹ : 3400, 1601, 1586, 1462

NMR (DMSO-d₆) 500 MHz δ: 2.01 (1H, m), 2.31 (3H, sX2), 2.33 (1H, m),2.50 (3H, sX2), 2.57 (3H, sX2) 2.78-2.97 (5H, m), 3.05-3.08 (1H, m),3.16-3.30 (2H, m), 3.60 (1H, m), 6.53 (1H, m), 6.79 (1H, m), 6.89-6.99(3H, m), 7.01-7.06 (1H, m), 7.21 (1H, m), 9.25 (1H, sX2), 9.65 (1H,brsX2), 10.48 (1H, sX2)

Mass (FAB): 347 (M⁺ 1)

Elementary analysis

    ______________________________________                                        For C.sub.23 H.sub.26 N.sub.2 O.0.9CH.sub.3 SO.sub.3 H.0.1H.sub.2 O                     C    H           N      S                                           ______________________________________                                        Calculated  64.68  7.00        6.31 6.50                                      Found       64.50  6.93        6.62 6.47                                      ______________________________________                                    

REFERENTIAL EXAMPLE 12-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline 15 ##STR33##

In an atmosphere of argon, 60 mg of proton sponge was dissolved in 2 mlof anhydrous dichloroethane. The resultant solution was cooled to 0° C.and 0.03 ml of 2,2,2-trichloroethyl chloroformate was added to thecooled solution. The produce mixture and a solution of 50 mg of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline in 0.5 ml anhydrous dichloroethaneadded dropwise thereto were stirred at room temperature for 30 minutes.The produced mixture was distilled under a vacuum to expeldichloroethane. The residue and 30 ml of ethyl acetate added theretowere washed with 1N hydrochloric acid and water, dried, andconcentrated, to afford 90 mg of an oily substance. When this oilysubstance was refined by column chromatography ]silica gel:hexane/ethylacetate (3:1)], 73 mg of the captioned compound was produced (yield91.8%).

IR (Liquid film method) cm⁻¹ : 1715, 1431, 1243, 1125, 754, 717

NMR (CDCl₃) 400 MHz δ: 1.80 (1H, m), 2.03 (1H, m), 2.13 (1H, m), 2.26(1H, m), 2.31-2.43 (4H, m) 2.85 (1H, m), 2.96 (1H, d, J=13.7 Hz), 3.54(1H, m), 3.81 (3H, s), 4.02 (1H, m), 4.18 (1H, m), 4.71-4.81 (2H, m),6.75 (1H, m), 6.95-6.98 (2H, m), 7.25 (1H, m)

Mass (EI): 433 (M⁺)

EXAMPLE 152-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline 16 ##STR34##

In an atmosphere of argon, 100 mg of2-(2,2,2-trichloroethoxycarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 25 μl of phenylhydrazine were dissolved in 3 ml of ethanol and theresultant solution was heated to 80° C. The hot solution consequentlyobtained and 0.15 ml of methanesulfonic acid added thereto were stirredat 80° C. for 40 minutes and then cooled to room temperature. Theproduced mixture was distilled under a vacuum to expel ethanol. Theresidue of the distillation was combined with 5 ml of a saturatedaqueous solution of sodium hydrogen carbonate and extracted three timeswith 20 ml of chloroform. The organic layers consequently separated werecombined, washed with a saturated aqueous saline solution, dried, andconcentrated, to afford 130 mg of an oily substance. When this oilysubstance was refined by column chromatography [silica gel:hexane/ethylacetate (3:1)], 104 mg of crude crystals were obtained. The crudecrystals, on being recrystallized from ethyl acetate, produced 60 mg ofthe captioned compound in a purified state (m.p. 197° to 198° C.) (yield51.3%).

IR (KBr) cm⁻¹ : 3410, 1707, 1441, 1245, 1127, 752

NMR (CDCl₃) 400 MHz δ: 1.84 (1H, td, J=13.2 Hz, 3.9 Hz), 2.38-2.46 (2H,m), 2.88-3.03 (4H, m), 3.11 (1H, 3, J=14.7 Hz), 3.48 (1H, m) 3.68 (3H,s), 4.11 (1H, m) 4.28 (1H, m), 4.72-4.82 (2H, m), 6.65 (1H, m),6.99-7.02 (2H, m), 7.05-7.14 (3H, m), 7.21 (1H, m), 7.44 (1H, m), 7.60(1H, m)

Mass (EI): 506 (M⁺)

Elementary analyses

    ______________________________________                                        For C.sub.25 H.sub.25 Cl.sub.3 N.sub.2 O.sub.3                                          C    H           N      S                                           ______________________________________                                        Calculated  59.13  4.96        5.52 20.94                                     Found       59.12  5.14        5.54 20.70                                     ______________________________________                                    

Similarly,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using p-tollyl hydrazine instead of phenylhydrazine,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using m-tollyl hydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using o-tollyl hydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-chlorophenylhydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-chlorophenylhydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-chlorophenylhydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is producedby using 4-bromophenylhydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-bromophenyl hydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-bromophenylhydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-nitrophenylhydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-nitrophenylhydrazine instead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-nitrophenylhydrazineinstead,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using 1-methyl-1-phenylhydrazine instead, and2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-phenyl-indolo[2,3-g]isoquinolineis produced by using 1,1-diphenylhydrazine instead.

EXAMPLE 162-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline17 ##STR35##

In an atmosphere of argon, 100 mg of2-(2,2,2-trichloroethoxycarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinewas dissolved in 2 ml of acetic acid. The resultant solution and 130 mgof zinc dust added thereto were stirred at room temperature for 22hours. The produced mixture was filtered to expel zinc, distilled undera vacuum to expel acetic acid, combined with 5 ml of a saturated aqueoussolution of sodium hydrogen carbonate, and extracted three times from 20ml of chloroform. The organic layers consequently separated werecombined, washed with a saturated aqueous saline solution, dried, andconcentrated, to afford a reaction mixture. In an atmosphere of argon,50 mg of the reaction mixture was dissolved in 5 ml of anhydrousdichloromethane. The produced solution and 60 μl of triethylamine and 35μl of cyclopropanecarbonyl chloride added thereto were stirred at roomtemperature for one hour. The resultant mixture was distilled under avacuum to expel dichloromethane, combined with 5 ml of a saturatedaqueous solution of sodium hydrogen carbonate, and extracted three timesfrom 20 ml of chloroform. The organic layers consequently separated werecombined, washed with a saturated aqueous saline solution, dried, andconcentrated, to afford 65 mg of an oily substance. When this oilysubstance was refined by column chromatography [silica gel;chloroform-chloroform/methanol (99/1)], 55 mg of crude crystals wereobtained. The crude crystals, on being recrystallized fromchloroform-hexane, produced 37 mg of the captioned compound in apurified form [m.p. 247° C. to 249° C. (decomposition)] (yield 46.9%).

IR (KBr) cm⁻¹ : 3408, 3238, 1609, 1582, 1491, 1460, 1255, 1228

NMR (CDCl₃) 500 MHz δ: 0.75-0.78 (2H, m), 0.95-1.12 (2H, m), 1.75-1.87(2H, m), 2.37-2.48 (1H, M), 2.85-3.30 (6H, m) 3.68 (3H, s), 4.05-4.72(2H, br) 6.65 (1H, m), 7.01-7.14 (5H, m), 7.22 (1H, d, J=7.9 Hz), 7.44(1H, d, J=6.7 Hz), 7.62 (1H. brs)

Mass (EI): 400 (M⁺)

Elementary analyses

    ______________________________________                                        For C.sub.26 H.sub.28 N.sub.2 O.sub.2                                                  C           H      N                                                 ______________________________________                                        Calculated 77.97         7.05   6.99                                          Found      77.77         7.34   6.64                                          ______________________________________                                    

Similarly,2-acryloyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using acryloyl chloride instead of cyclopropane carbonylchloride,2benzoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using benzoyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using phenylacetyl chloride instead,2-acetyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using acetyl chloride instead,2-propionyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using propionyl chloride instead,2-butyryl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indro[2,3-g]isoquinolineis produced by using butyryl chloride instead,2-thiophenecarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-thiophenecarbonyl chloride instead,2-valeryl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using valeryl chloride instead,2-furoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-furoyl chloride instead,2-cyclobutylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using cyclobutanecarbonyl chloride instead,2-p-tolyoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using p-toluoyl chloride instead,2xyloyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2xyloyl chloride instead, and2-(p-anisoyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using p-anisolyl chloride instead. Similarly,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline isproduced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-cyclopropylcarbonyl-4aα-(3-methoxyphednyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead. Similarly,2acryloyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead and acryloyl chloride instead of2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand cyclopropanecarbonyl chloride,2acryloyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline andacryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead, 2acryloyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is producedby using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryl acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead,2acryloyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand acryloyl chloride instead, and2acryloyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6methyl-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineand acryloyl chloride instead.

Similarly,2benzoyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride, 2benzoyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is producedby using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2benzoyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and benzoyl chloride instead,2-benzoyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2-benzoyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride,2-benzoyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2-benzoyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and benzoyl chloride instead,2-benzoyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2-benzoyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2-benzoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineand benzoyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinoline is produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline and phenylacetylchloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinoline is producedby using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead, 2-phenylacetyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using 2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead, and2-phenylacetyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineand phenylacetyl chloride instead.

EXAMPLE 172-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline18 ##STR36##

In an atmosphere of argon, 6mg of lithium aluminum hydride was suspendedin 1 ml of anhydrous THF, the produced suspension was cooled to 0° C.,and combined with 20 mg of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline.The resultant mixture was heated to room temperature, stirred at thistemperature for one hour, cooled to 0° C., and combined with ethylacetate and a saturated aqueous solution of potassium sodium tartrate.The mixture was filtered to expel impurities and distilled under avacuum to expel ethyl acetate by vaporaization, to obtain 20 mg of anoily substance. When this oily substance was refined by columnchromatography [silica gel; chloroform-methanol/28% aquaammonia/chloroform (3:0.1:97)], it produced 18 mg of the captionedcompound (yield 93.2%). When this compound was recrystallized fromchloroform-hexane, 10 mg of the compound in a purified form (m.p. 163.5°to 165.5° C.) was obtained.

IR (KBr) cm⁻¹ : 2928, 2900, 2842, 1607, 1580

NMR (CDCl₃) 400 MHz δ: 0.11 (2H, m), 0.52 (2H, m), 0.91 (1H, m),1.99-2.10 (2H, m), 2.24-2.35 (2H, m), 2.38-2.41 (1H, m), 2.58-2.67 (2H,m), 2.88-3.03 (4H, m), 3.07 (1H, d, J=15.6 hz), 3.19 (1H, m), 3.67 (3H,s), 6.61 (1H, m), 7.01-7.10 (5H, m), 7.20 (1H, m), 7.43 (1H, m), 7.66(1H, brs)

Mass (m/e): 386 (M⁺)

Elementary analyses

    ______________________________________                                        For C.sub.26 H.sub.30 N.sub.2 O                                                        C           H      N                                                 ______________________________________                                        Calculated 80.79         7.82   7.25                                          Found      80.11         7.76   7.19                                          ______________________________________                                    

Similarly,2-allyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2phenethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-ethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acetyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-propyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-propionyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-butyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-butyryl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-thienylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-thiopenecarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-pentyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using 2-valeryl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-furylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-furoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2cyclobutylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-cyclobutylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-(p-methylbenzyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(p-toluoyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-(4-methoxybenzyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using 2-(p-anisoyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-(3-methoxybenzyl)4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-(m-anisoyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead. Similarly,2-allyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-allyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinoline isproduced by using2-acryloyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using 2-acryloyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-allyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-allyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-allyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

Similarly,2-benzyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinoline is produced by using2-benzoyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-benzyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinoline is produced by using2-benzoyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-benzyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-benzoyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

Similarly,2-phenethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using 2-phenylacetyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-phenethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-phenethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinoline is produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using 2-phenylacetyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-phenethyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo-2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline instead.

EXAMPLE 182-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline19 ##STR37##

A solution of 128 mg (0.33 mmol) of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo2,3-g]isoquinoline,0.2 ml (2.20 mmol) of n-propanethiol, 225 mg (2.0 mmol) ofpotassium-t-butoxide in DMF was heated and stirred at 125° C. Four hoursthereafter, the solution and 0.2 ml (2.2 mmol) of n-propanethiol and 225mg (2.0 mmol) of potassium-t-butoxide added thereto was stirred at 125°C. for four hours. The resultant reaction mixture was cooled to roomtemperature and then concentrated. The concentrate was combined with asaturated aqueous solution of sodium hydrogen carbonate and extractedform a chloroform-methanol (3:1) mixture. When the organic layersconsequently formed were combined, washed with a saturated aqueoussaline solution, dried, and concentrated, it produced a powder. Whenthis powder was separated and refined by column chromatography (silicagel:chloroform:methanol:28% aqua ammonia=95:5:0.1-90:10:0.1), 84 mg ofthe captioned compound was obtained. This compound was suspended inmethanol, converted by addition of methanesulfonic acid into amethane-sulfonate, and recrystallized from methanol-chloroform.Consequently, 59 mg of the methanesulfonate of the captioned compound ina purified form (m.p.>250° C.) was obtained.

IR (KBr) cm⁻¹ : 3390, 1586, 1046

NMR (DMSO-d₆) 400 MHz δ: 0.38 (2H, br), 0.63 (2H, br), 1.07 (1H, m),2.07 (1H, m), 2.31 (3H, s), 2.54-2.65 (3H, m), 2.88-3.05 (5H, m), 3.11(1H, d, J=16.5 Hz), 3.37 (1H, m), 3.51 (1H, m), 3.74 (1H, m), 6.54 (1H,m), 6.90-6.99 (4H, m), 7.04 (1H, t, J=7.9 Hz), 7.19 (1H, d, J=7.9 Hz),7.34 (1H, d, J=7.3 Hz), 9.26 (1H, s), 9.38 (1H, br), 10.62 (1H, s)

Mass (FAB): 373 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.25 H.sub.28 N.sub.2 O.CH.sub.3 SO.sub.3 H                                     C    H           N      S                                           ______________________________________                                        Calculated  66.64  6.88        5.98 6.84                                      Found       66.32  6.93        6.05 6.76                                      ______________________________________                                    

Similarly,2-benzyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-phenethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-ethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-ethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-propyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-propyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-butyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-butyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-thienylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-thienylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-pentyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-pentyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-furylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-furylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclobutylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclobutylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-(4-tollylmethyl)-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is producedby using2-(4-tollylmethyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

Similarly,2-benzyl-4aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-benzyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline isproduced by using2-benzyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is produced by using2-benzyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-benzyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-benzyl-4aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-benzyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-benzyl-4aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

Similarly,2-phenethyl-4aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-phenethyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is producedby using2-phenethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-phenethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indro[2,3-g]isoquinoline instead,2-phenethyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-phenethyl-4aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline isproduced by using2-phenethyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is produced by using2-phenethyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-phenethyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-phenethyl-4aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-phenethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 192-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-6H-indolo[2,3-g]isoquinoline20 ##STR38##

By subjecting 300 mg of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 168 mg of p-tollyl hydrazine hydrochloride to the procedure ofExamples 15 to 17, 60 mg of the captioned compound was produced.

IR (KBr) cm⁻¹ : 2922, 1605, 1580, 1464

NMR (CDCl₃) 400 MHz δ: 0.10-0.16 (2H, m), 0.13 (1H, m), 0.51-0.57 (2H,m), 2.02-2.13 (2H, m), 2.27-2.40 (3H, m), 2.42 (3H, s), 2.55-2.67 (2H,m), 2.83-3.06 (5H, m) 3.18 (1H, m), 3.67 (3H, s), 6.60 (1H, m), 6.89(1H, dd, J=8.6 Hz, 1.2 Hz), 7.00-7.02 (2H, m), 7.06-7.10 (2H, m), 7.26(1H, s), 7.62 (1H, brs)

Mass (m/e): 400 (M⁺)

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-methylphenyl hydrazine instead of 4-methylphenylhydrazine and2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced using 2-methylphenyl hydrazine instead.

EXAMPLE 202-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-6H-indolo[2,3-g]isoquinoline21 ##STR39##

A solution of 105 mg (0.26 mmol) of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-6H-indolo[2,3-g]isoquinoline,0.27 ml (2.98 mmol) of n-propane thiol, and 300 mg (2.67 mmol) ofpottassium-t-butoxide in 5 ml of DMF was heated and stirred at 125° C.for four hours. The resultant reaction mixture was cooled to roomtemperature and concentrated. The residue was combined with a saturatedaqueous solution of sodium hydrogen carbonate and extracted three timesfrom chloroform-methanol (3:1). The organic layers consequentlyseparated were combined, washed with a saturated aqueous salinesolution, dried, and concentrated, to afford a powder. This powder wasdissolved in methanol, combined with methanesulfonic acid, concentrated,and separated and refined by column chromatography [Sephadex, LH-20;methanol], to obtain 85 mg of the methanesulfonate of the captionedcompound in a purified form (yield 67.2%).

IR (KBr) cm⁻¹ : 3270, 1657, 1586, 1460

Mass (FAB): 387 (M⁺ +1)

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

REFERENTIAL EXAMPLE 22-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline22 ##STR40##

In an atmosphere of argon, 3.28 of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinewas dissolved in 50 ml of acetic acid. the produced solution and 4.90 gof zinc dust added thereto were stirred at room temperature for fourhours. The resultant mixture was filtered to remove zinc, distilledunder a vacuum to expel acetic acid, combined with 30 ml of an aqueous1N sodium hydroxide solution, and extracted four times from 50 ml ofchloroform. The organic layers consequently separated were combined,washed with a saturated aqueous saline solution, dried, andconcentrated, to obtain 1.98 g of the reaction mixture. In an atmosphereof argon, this reaction mixture was dissolved in 50 ml of anhydrousdichloromethane. The produced solution and 2.1 ml of triethylamine and0.9 ml of cyclopropanecarbonyl chloride added thereto were stirred atroom temperature for three hours. The resultant mixture was washed with1N hydrochloric acid and water, dried, and concentrated, to produce 2.86g of an oily substance. This oily substance was refined by columnchromatography [silica gel:chloroform/ethyl acetate (9/1)], to afford1.77; g of the captioned compound (Yield 75.3%).

IR (Liquid film method) cm⁻¹ : 2948, 1713, 1632, 1582, 1450, 1245

EI - MS (m/z): 327 (M⁺)

NMR (CDCl₃) 400 MHz δ: 0.72-0.81 (2H, m), 0.96-1.30 (2H, m), 1.72-2.47(9H, m), 2.76 (0.5 H, m), 2.97 (1H, d, J=14.2 Hz), 3.07 (0.5H, m), 3.27(0.5H, m), 3.75 (0.5H, m), 3.79 (3H, s), 4.01 (0.5H, m), 4.12 (0.5 H,m), 4.33 (0.5 H, m), 4.60 (0.5 H, m), 6.75 (1H, dd, J=8.3 Hz, 2.0 Hz),6.95-7.01 (2H, m), 7.25 (1H, t, J=8.3 Hz)

Similarly,2-acryloyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using acryloyl chloride instead of cyclopropane carbonylchloride,2-benzoyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using benzoyl chloride instead,2-phenylacetyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a.beta.-decahydroisoquinolineis produced by using phenylacetyl chloride instead,2-acetyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a.beta.-decahydroisoquinolineis produced by using acetyl chloride,2-propionyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using propionyl chloride instead,2-butyryl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using butyryl chloride instead, 2-thiophenecarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using 2-thiophene carbonyl chloride instead,2-valeryl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline is produced by using valeryl chloride instead,2-furoyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8aβ-decahydroisoquinolineis produced by using 2-furoyl chloride instead, 2-cyclobutylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8aβ-decahydroisoquinolineis produced by using cyclobutane carbonyl chloride instead,2-(p-toluoyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8aβ-decahydroisoquinolineis produced by using p-toluoyl chloride instead,2-xyloyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8aβ-decahydroisoquinolineis produced by using xyloyl chloride instead, and2-(p-anisoyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8aβ-decahydroisoquinolineis produced by using p-anisoyl chloride instead.

EXAMPLE 212-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline23 ##STR41##

In an atmosphere of argon, 185 mg of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8aβ-decahydroisoquinolineand 75 μl of 1-methyl-1-phenyl hydrazine were dissolved in 3 ml ofethanol and the produced solution was heated to 80° C. The hot solutionand 0.37 ml of methanesulfonic acid added thereto were stirred at 80° C.for 15 minutes and then cooled to room temperature. The resultantmixture was distilled under a vacuum to expel ethanol, combined with 10ml of a saturated aqueous solution of sodium hydrogen carbonate, andextracted three times from 20 ml of chloroform. The organic layersconsequently separated were combined, washed with a saturated aqueoussaline solution, dried, and concentrated, to obtain 330 mg of an oilysubstance. When this oily substance was refined by column chromatography[silica gel; dichloromethane/ether (19/1)], 162 mg of crude crystalswere obtained. When the crude crystals were recrystalized from ethylacetate-hexane, 141 mg of the captioned compound in a purified formhaving a m.p. of 131° to 132.5° C. (yield 60.2%) was obtained.

IR (KBr) cm⁻¹ : 1634, 1470, 1441, 1261, 1245, 1228, 735

EI - MS (m/z): 414 (M⁺), 157

NMR (CDCl₃) 400 MHz δ: 0.75-0.79 (2H, m), 0.95-1.03 (2H, m), 1.76-1.89(2H, m), 2.38 (1H, m), 2.50 (1H, m), 2.80 (1H, m), 2.95-3.06 (3H, m),3.22 (1H, d, J=15.6 Hz), 3.40-3.49 (1H, brm), 3.55 (3H, s), 3.69 (3H,s), 4.24-4.31 (1H, brm), 4.39-4.48 (1H, brm), 6.66 (1H, m), 7.03-7.08(3H, m), 7.11-7.15 (2H, m), 7.21 (1H, d, J=7.9 Hz), 7.15 (1H, d, J=7.6Hz)

Similary,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)1,2,3,4,4a,5,11,11aβ-octahydro-6-phenyl-indolo[2,3-g]isoquinolineis produced using 1,1-diphenyl hydrazine instead of 1-methyl-1-phenylhydrazine,2-acryloyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced using2-acryloyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineinstead of 2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβdecahydroisoquinoline,2-benzoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using 2-benzoyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline instead, and2-phenylacetyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,6,7,8,8aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using2phenylacetyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a.beta.-decahydroisoquinolineinstead.

EXAMPLE 222-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline24 ##STR42##

In an atmosphere of argon, 35 mg of lithium aluminum hydride wassuspended in 5 ml of anhydrous THF and cooled to 0° C. and a solution of150 mg of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6-methyl-indolo[2,3-g]isoquinolinein 2 ml of anhydrous THF was dropped into the cooled suspension. Theproduced mixture was heated to room temperature, stirred for two hours,cooled to 0° C., and combined with ethyl acetate and a saturated aqueoussolution of potassium sodium tartrate. When the resultant mixture wasfiltered to remove the insolubles and then distilled under a vacuum toexpel ethyl acetate, 140 mg of an oily substance was obtained. When thisoily substance was refined by column chromatography [silica gel;chloroform-chloroform/methanol (99/1)], 131 mg of the captioned compoundwas obtained. When this compound was recrystallized from ethyl acetate,110 mg of the compound in a purified form (m.p. 133° to 134° C.) (yield75.9%) was obtained.

IR (KBr) cm⁻¹ : 3420, 1601, 1475, 1386, 1251, 764

EI - MS (m/z): 400 (M⁺), 157

NMR (CDCl₃) 400 MHz δ: 0.16-0.21 (2H, m), 0.56-0.61 (2H, m), 1.02 (1H,m), 2.20-2.27 (2H, m), 2.40-2.50 (3H, m), 2.70-2.78 (2H, m), 2.85 (1H,brd, J=16.1 Hz), 3.00-3.04 (2H, m), 3.13-3.18 (2H, brm), 3.31 (1H, m),3.51 (3H, s), 3.68 (3H, s), 6.63 (1H, m), 7.02-7.14 (5H, m), 7.19 (1H,d, J=8.3 Hz), 7.44 (1H, d, J=7.3 Hz)

Similarly,2-allyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using2-acryloyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead of 2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced using2-benzoyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead, and2-phenethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using2-phenylacetyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 232-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline25 ##STR43##

In an atmosphere of argon, 120 mg of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,0.2 ml of n-propane thiol, and 230 mg of potassium-t-butoxide weredissolved in 3 ml of anhydrous DMF and the produced solution was stirredat 130° C. Four hours thereafter, the resultant mixture and 0.2 ml ofn-propane thiol and 230 mg of potassium-t-butoxide added thereto by wayof replenishment were stirred at 130° C. for two hours and subsequentlycooled to room temperature. The produced mixture was distilled under avacuum to expel DMF, combined with 5ml of water, and extracted threetimes from 20 ml of chloroform. The organic layers consequentlyseparated were combined, washed with a saturated aqueous salinesolution, dried, and concentrated, to produce 120 mg of a powder. Thispowder was suspended in 3 ml of methanol, combined with 20 μl ofmethanesulfonic acid, and dissolved by addition of DMF. The resultantmixture was distilled under a vacuum to expel DMF, combined with ethylacetate, and filtered to separate a solid content. When this solid wasrecrystallized from methanol, 74 mg of the methanesulfonate of thecaptioned compound (decomposed at 250° C.) (yield 51.4%) was obtained.

IR (KBr) cm⁻¹ : 3410, 1601, 1474, 1212, 1170, 1042, 784, 555

FAB - MS (m/z): 387 (M⁺ +1)

NMR (DMSO-d₆) 500 MHz : 0.36-0.41 (2H, m), 0.62-0.66 (2H, m), 1.07 (1H,m), 2.10 (1H, m), 2.30 (3H, m), 2.56-2.67 (3H, m), 2.85 (1H, m), 2.92(1H, m), 2.98-3.08 (3H, m), 3.29-3.38 (2H, m), 3.53 (3H, s), 3.51-3.55(1H, m), 3.75 (1H, m), 6.55 (1H, m), 6.94-6.99 (3H, m), 7.03-7.07 (2H,m), 7.31 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=7.9 Hz), 9.25 (1H, s), 9.37(1H, br)

Elementary Analysis

    ______________________________________                                        For C.sub.26 H.sub.30 N.sub.2 O.CH.sub.3 SO.sub.3 H.0.37H.sub.2 O                       C    H           N      S                                           ______________________________________                                        Calculated  66.28  7.16        5.73 6.55                                      Found       66.27  7.18        5.69 6.65                                      ______________________________________                                    

Similarly,2-benzyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using2-benzyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinoline,and2-phenethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced using2-phenethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 242-Cyclopropylcarbon-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinoline26 ##STR44##

In an atmosphere of argon, 406 mg of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 267 mg of 2-fluorophenyl hydrazine hydrochloride were dissolved in 5ml of ethanol and the produced solution was heated to 80° C. Theresultant mixture and 0.94 ml of methanesulfonic acid added thereto werestirred at 80° C. for 30 minutes and then cooled to room temperature.The cooled mixture was alkalinized by addition of a saturated aqueoussolution of sodium hydrogen carbonate and extracted three times from 50ml of chloroform. The organic layers consequently separated werecombined, washed with a saturated aqueous saline solution, dried, andconcentrated, to afford 684 mg of an oily substance. When this oilysubstance was separated and refined by column chromatography [silicagel; cyclohexane/ethyl acetate (2/1 - 1/1)], 291 mg of crude crystalswas obtained. When the crude crystals were recrystallized fromchloroform-cyclohexane, 254 mg of the captioned compound having a m.p.of 275°-277° C. (colored in the neighborhood of 260° C.) (yield 48.9%)was obtained.

IR (KBr) cm⁻¹ : 3252, 1619, 1581, 1460, 1249, 1228

EI - MS (m/z): 418 (M⁺), 161

NMR (CDCl₃) 400 MHz δ: 0.76-0.79 (2H, m), 0.95-0.14 (2H, m), 1.75-1.90(2H, m), 2.35-2.49 (2H, m), 2.77-3.01 (4H, m), 3.08-3.25 (2H, m), 3.69(3H, s), 3.97-4.74 (2H, brm), 6.67 (1H, m), 6.80 (1H, dd, J=10.7 Hz, 7.8Hz), 6.96 (1H, td, J=7.8 Hz, 4.9 Hz), 7.00-7.19 (2H, m), 7.14 (1H, t,7.8 Hz), 7.19 (1H, d, J=7.8 Hz), 7.8 (1H, brs)

Similarly,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-fluorophenyl hydrazine instead of 2-fluorophenylhydrazine, and2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-fluorophenyl hydrazine instead.

EXAMPLE 252-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinoline27 ##STR45##

In an atmosphere of argon, 3.10 g of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 1.39 g of 2-fluorophenyl hydrazine were dissolved in 40 ml ofethanol and the produced solution was heated to 80° C. The resultantmixture and 4.6 ml of methanesulfonic acid added thereto were stirred at80° C. for 15 minutes and then cooled to room temperature. The mixturewas distilled under a vacuum to expel ethanol, alkalinized by additionof an aqueous 1N sodium hydrogen solution, and extracted four times from50 ml of chloroform. The organic layers consequently separated werecombined, washed with a saturated aqueous saline solution, dried, andconcentrated to afford 4.11 g of an oily substance. When this oilysubstance was separated and refined by column chromatography [silicagel; dichloromethane/cyclohexane (1/1)-dichloromethane], 3.00 g of crudecrystals was obtained. When these crude crystals were recrystallizedfrom ethyl acetate, 2.08 g of the captioned compound having a m.p. of235° to 237° C. (yield 55.5%) was obtained.

IR (KBr) cm⁻¹ : 3332, 1694, 1460, 1435, 1259, 1226, 1149, 1131, 1046,777, 717

EI - MS (m/z): 524 (M⁺), 526, 161

NMR (CDCl₃) 500 MHz δ: 1.85 (1H, m), 2.39-2.46 (2H, m), 2.88-2.99 (4H,m), 3.14 (1H, m), 3.49 (1H, m), 3.69 (3H, s), 4.10 (1H, m), 4.28 (1H,brd, J=13.4 Hz), 4.72-4.82 (2H, m), 6.66 (1H, m), 6.80 (1H, dd, J=11.0Hz, 7.9 Hz), 6.94-7.01 (3H, m), 7.14 (1H, t, J=7.9 Hz), 7.20 (1H, m),7.77 (1H, brd, J=7.3 Hz)

Similarly,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-fluorophenyl hydrazine instead of 2-fluorophenylhydrazine, and2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-fluorophenyl hydrazine instead.

EXAMPLE 262-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinoline26 ##STR46##

In an atmosphere of argon, 2.22 g of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinewas suspended in 40 ml of acetic acid and the produced suspension and2.75 g of zinc dust added thereto were stirred at room temperature forthree hours. The resultant mixture was filtered to remove zinc anddistilled under a vacuum to expel acetic acid, alkalinized by additionof an aqueous 1N sodium hydrogen solution, and extracted three timesfrom 50 ml of chloroform. The organic layers consequently separated werecombined, washed with a saturated aqueous saline solution, dried, andconcentrated, to prepare 1.70 g of a reaction mixture. This reactionmixture was suspended in 40 ml of and 1.20 ml of triethylamine and 0.57ml of cyclopropanecarbonyl chloride added thereto were stirred at roomtemperature for two hours. The resultant mixture was distilled under avacuum to expel dichloromethane. The distillate was combined with 20 mlof ethyl acetate and 20 ml of an aqueous 1N sodium hydroxide solution toinduce precipitation of a solid substance. By separating this solidsubstance from the reaction mixture by means of filtration, 1.51 g ofthe captioned compound was obtained. In the meantime, the filtrate wasdivided into two layers and extracted three times from 20 ml ofchloroform. The organic layers consequently separated were combined,washed with a saturated aqueous saline solution, dried, andconcentrated, to obtain 550 mg of an oily substance. When this oilysubstance was separated and refined by column chromatography [silicagel; chloroform], 180 mg of the captioned compound (yield 95.6%) wasobtained. Various spectral data obtained from the compound supportidentity of this compound compares with the compound obtained in Example24.

Similarly,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead.

EXAMPLE 272-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinoline28 ##STR47##

In an atmosphere of argon, 215 g of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinewas suspended in 20 ml of anhydrous THF, cooled to 0° C., and combinedwith 60 mg of lithium aluminum hydride. The resultant mixture was heatedto room temperature, stirred for one hour, cooled to 0° C., combinedwith ethyl acetate and a saturated aqueous solution of potassium sodiumtartrate. The mixture was filtered to remove insolubles and distilledunder a vacuum to expel ethyl acetate and produce 210 mg of crudecrystals. When these crude crystals were recrystallized fromchloroform-ether, 170 mg of the captioned compound having a m.p. of 137°to 139° C. (yield 81.8%) was obtained.

IR (KBr) cm⁻¹ : 2836, 1578, 1241, 1228, 1050, 779

EI - MS (m/z): 404 (M⁺), 242

NMR (CDCl₃) 500 MHz δ: 0.07-0.12 (2H, m), 0.48-0.54 (2H, m), 0.88 (1H,m), 1.97-2.07 (2H, m), 2.23-2.32 (2H, m), 2.40 (1H, m), 2.54-2.65 (2H,m), 2.89-3.02 (4H, m), 3.10 (1H, d, J=15.9 Hz), 3.16 (1H, m), 3.68 (3H,s), 6.62 (1H, m), 6.78 (1H, dd, J=7.9 Hz, 11.0 Hz), 6.94 (1H, td, J=7.9Hz, 4.9 Hz), 7.02-7.04 (2H, m), 7.09 (1H, t, J=7.9 Hz), 7.19 (1H, d,J=7.3 Hz), 7.80 (1H, brs)

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 282-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinoline29 ##STR48##

In an atmosphere of argon, 164 g of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,0.31 ml of n-propane thiol, and 350 mg of potassium-t-butoxide weredissolved in 5 ml of anhydrous DMF and stirred at 230° C. for 4.5 hours.The produced solution was cooled to room temperature, then distilledunder a vacuum to expel DMF, combined with 5 ml of water and extractedthree times from 15 ml of chloroform. The organic layers consequentlyseparated were combined, washed with a saturated aqueous salinesolution, dried, and concentrated, to produce 155 mg of a powder. Thispowder was suspended in 2 ml of methanol, converted into amethanesulfonated by addition of 25 μl of methanesulfonic acid, andseparated and refined by column chromatography [Sephadex,LH-20;methanol], to afford 125 mg of crude crystals. When these crudecrystals were recrystallized from ethanol, 51 mg of the methanesulfonateof the captioned compound (decomposed at 240° C. (yield 25.9%) wasobtained.

IR (KBr) cm⁻¹ : 3180, 1601, 1460, 1330, 1210, 1046, 785

FAB - MS (m/z): 391 (M⁺ +1)

NMR (DMSO-d₆) 500 MHz δ: 0.35-0.40 (2H, m), 0.62-0.67 (2H, m), 1.06 (1H,m), 2.07 (1H, m), 2.31 (3H, s), 2.55-2.67 (3H, m), 2,89-3.07 (5H, m),3.14 (1H, d, J=15.8 Hz), 3.38 (1H, m), 3.51 (1H, m), 3.73 (1H, m ), 6.54(1H, m), 6.81 (1H, dd, J=11.6 Hz, 7.9 Hz), 6.88-6.94 (3H, m) , 7.04 (1H,t, J=7.9 Hz), 7.17 (1H, d, J=7.9 Hz), 9.26 (1H, s), 9.39 (1H, br), 11.09(1H, s)

Elementary analysis

    ______________________________________                                        For C.sub.25 H.sub.27 N.sub.2 OF.CH.sub.3 SO.sub.3 H                                  C       H      N         F    S                                       ______________________________________                                        Calculated                                                                              64.18     6.42   5.76    3.90 6.59                                  Found     64.25     6.46   5.79    3.79 6.73                                  ______________________________________                                    

Similarly,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline, and2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 292-Allyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinoline30 ##STR49##

In an atmosphere of argon, 130 mg of2-(2,2,2-trichloroethoxycarbonyl)--4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinewas dissolved in 5 ml of acetic acid and the produced solution and 170mg of zinc dust added thereto were stirred at room temperature for twohours. The resultant mixture was filtered to remove zinc, distilledunder a vacuum to expel acetic acid, then combined with 10 ml of asaturated aqueous solution of sodium hydrogen carbonate, and extractedthree times from 30 ml of chloroform/methanol (3/1). The organic layersconsequently separated were combined, washed with a saturated aqueoussaline solution, dried, and concentrated, to produce a reaction mixture.In an atmosphere of argon, 100 mg of the reaction mixture was dissolvedin 5 ml of anhydrous DMF and the produced solution and 35 mg of sodiumhydrogen carbonate and 23 μl of allyl bromide added thereto werethermally refluxed for 30 minutes. The resultant reaction solution wascooled to room temperature, combined with 10 ml of water, and extractedthree times from 30 ml of chloroform. The organic layers consequentlyseparated were combined, washed with a saturated aqueous salinesolution, dried, and concentrated, to afford 120 mg of an oilysubstance. When this oily substance was separated and refined by columnchromatography [silica gel; chromoform/methanol (97/3)], 77 mg of crudecrystals was produced. When these crude crystals were recrystallizedfrom ethyl acetate, 54 mg of the captioned compound having a m.p. of188° to 189° C. (yield 56.6%) was obtained.

IR (KBr) cm⁻¹ : 2930, 2838, 1609, 1578, 1460, 1294, 1238, 1042, 741

EI - MS (m/z): 372 (M⁺), 143

NMR (CDCl₃) 500 MHz δ: 1.94-2.09 (2H, m), 2.39 (1H, m), 2.55-2.64 (2H,m), 2.80 (1H, m), 2.88-3.09 (7H, m), 3.68 (3H, s), 5.13-5.20 (2H, m),5.91 (1H, m), 6.61 (1H, m), 7.01-7.11 (5H, m), 7.21 (1H, m), 7.43 (1H,m), 7.58 (1H, brs)

Similarly,2-allyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-allyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline instead,2-allyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-allyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 302-Allyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-H-indolo[2,3-g]isoquinoline31 ##STR50##

In an atmosphere of argon, 130 mg of2allyl--4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinewas dissolved in 5 ml of anhydrous DMF and the produced solution and0.35 mg of n-propane thiol, and 390 mg of potassium-t-butoxide addedthereto were stirred at 130° C. for six hours. The resultant mixture wascooled to room temperature, distilled under a vacuum to expel DMF,combined with 5 ml of water and extracted three times from 20 ml ofchloroform. The organic layers consequently separated were combined,washed with a saturated aqueous saline solution, dried, andconcentrated, to afford 130 mg of an oily substance. When this oilysubstance was separated and refined by column chromatography [silicagel; chloroform/methanol/28% aqua ammonia (95/5/0.2)], 110 mg of a powerwas obtained. When this powder was suspended in 1 ml of methanol,converted into a methanesulfonate by addition of 22 μl ofmethanesulfonic acid, and separated and refined by column chromatography[Sephadex; LH-20; methanol], 130 mg of crude crystals was obtained. Whenthese crude crystals were recrystallized from methanol-ethanol, 67 mg ofthe methanesulfonate of the captioned compound (decomposed at 250° C.)(yield 42.2%) was obtained.

IR (KBr) cm⁻¹ : 3416, 1601, 1460, 1212, 1160, 1042

FAB - MS (m/z): 359 (M⁺ +1)

NMR (DMSO-d₆) 500 MHz δ: 2.03 (1H, m), 2.32 (3H, s), 2.54-2.62 (3H, m),2.87-3.02 (3H, m), 3.10 (1H, d, J=15.8 Hz), 3.30-3.41 (2H, m), 3.61 (1H,m), 3.79 (2H, m), 5.51-5.56 (2H, m), 5.92 (1H, m), 6.54 (1H, dd, J=7.9Hz, 1.8 Hz), 6.89-6.94 (3H, m), 6.98 (1H, m), 7.04 (1H, t, J=7.9 Hz),7.18 (1 H, d, J=7.9 Hz), 7.33 (1H, d, J=7.9 Hz), 9.26 (1H, s), 9.64 (1H,br), 10.61 (1H, s)

Elementary analysis

    ______________________________________                                        For C.sub.24 H.sub.26 N.sub.2 O.CH.sub.3 SO.sub.3 H.0.2H.sub.2 O                        C    H           N      S                                           ______________________________________                                        Calculated 65.53   6.69        6.11 7.00                                      Found      65.44   6.60        6.08 7.02                                      ______________________________________                                    

Similarly,2-allyl-4aα-(3-hydroxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-allyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is produced by using2-allyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-(allyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-allyl-4aα-(3-hydroxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline isproduced by using2-allyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline is produced by using2-allyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, 2-allyl-4aα-(3-hydroxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline isproduced by using2-allyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead,2-allyl-4aα-(3-hydroxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-allyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using2-allyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineinstead.

REFERENTIAL EXAMPLE 32-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-acetoxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline32 ##STR51##

In an atmosphere of argon, 2.64 g of proton sponge was dissolved in 60ml of anhydrous 1,2-dichloroethane and the produced solution was cooledto 0° C. and combined with 1.35 ml of 2,2,2-trichloroethylchloroformate. The resultant mixture and a solution of 2.61 g of2-methyl-4aα-(3-methoxyphenyl)-5-acetoxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinein 15 ml of anhydrous 1,2-dichloroethane added dropwise thereto wereheated to room temperature and stirred for 30 minutes. The mixture wasdistilled under a vacuum to expel 1,2-dichloroethane, combined with 60ml of ethyl acetate, washed with 20 ml of 1N hydrochloric acid and 20 mlof a saturated aqueous saline solution, dried, and concentrated, toafford 4.14 g of an oily substance. When this oily substance wasseparated and refined by column chromatography [silica gel;cyclohexane/ethyl acetate (4/1)], 950 mg of 6β-acetoxy form and 2.41 gof a mixture of 6α-acetoxy form and 6β-acetoxy form (yield 85.3%) wasobtained.

IR (Liquid film method) cm⁻¹ : 1717, 1433, 1241, 1125, 1033, 716

EI - MS (m/z): 477 (M⁺), 479, 481

NMR (CDCl₃) 500 MHz δ: 1.43-1.49 (2H, m), 1.65 (1H, td, J=13.2 Hz, 4.0Hz), 1.74 (1H, m), 1.83 (1H, m), 1.96 (3H, s), 2.05 (1H, brd, J=14.3Hz), 2.13-2.19 (2H, m), 2.47 (1H, m), 2.60 (1H, m), 3.58 (1H, m), 3.81(3H, s), 3.95 (1H, m), 4.07 (1H, m), 4.39 (1H, m), 4.68-4.78 (2H, m),6.74 (1H, dd, J=8.1 Hz, 2.2 Hz), 6.99-7.05 (2H, m), 7.26 (1H, t, J=8.1Hz)

REFERENTIAL EXAMPLE 42-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6β-acetoxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline33 ##STR52##

In an atmosphere of argon, 945 mg of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6β-acetoxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinewas dissolved in 20 ml of acetic acid, combined with 1.30 g of zincdust, and stirred at room temperature for 24 hours. The resultantmixture was filtered to remove zinc, distilled under a vacuum to expelacetic acid, alkalinized by addition of a saturated aqueous solution ofsodium hydrogen carbonate, and extracted three times from 50 ml ofchloroform. The organic layers consequently separated were combined,washed with a saturated aqueous saline solution, dried, and concentratedto produce 570 mg of a reaction mixture. In an atmosphere of argon, thisreaction mixture was dissolved in 20 ml of anhydrous dichloromethane andthe produced solution and 0.55 ml of triethylamine and 0.27 ml ofcyclopropanecarbonyl chloride added thereto were stirred at roomtemperature for two hours. When the resultant mixture was washed with 1Nhydrochloric acid and water, dried, and concentrated, and 790 mg of anoily substance was obtained. When this oily substance was separated andrefined by column chromatography [silica gel; chloroform/ethyl acetate(9/1)], 430 mg of the captioned compound (yield 58.6%) was obtained.

IR (Liquid film method) cm⁻¹ : 1731, 1634, 1439, 1243, 1031

EI - MS (m/z): 371 (M⁺)

NMR (CDCl₃) 400 MHz δ: 0.69-0.78 (2H, m), 0.92-1.00 (2H, m), 1.39-1.50(2H, m), 1.63 (1H, m), 1.69-1.82 (3H, m), 1.96 (3H, s), 2.04-2.18 (3H,m), 2.48 (1H, m), 2.55-2.72 (1H, br), 3.40-3.58 (1H, br), 3.81 (3H, s),4.01-4.43 (3H, m), 6.74 (1H, dd, J=8.3 Hz, 2.0 Hz), 7.01-7.06 (2H, m),7.26 (1H, t, J=8.1 Hz)

REFERENTIAL EXAMPLE 52-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-6β-hydroxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline34 ##STR53##

In an atmosphere of argon, 190 mg of lithium aluminum hydride wassuspended in 15 ml of anhydrous THF and cooled to 0° C. The cooledsuspension consequently formed and a solution of 430 mg of2-cyclopropylcarbon-4aα-(3-methoxyphenyl)-6β-acetoxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinein 5 ml of anhydrous THF added dropwise thereto were heated to roomtemperature and stirred for two hours. The resultant mixture was cooledto 0° C. and then combined with ethyl acetate and a saturated aqueoussolution of sodium tartrate. The mixture was filtered to removeinsolubles and distilled under a vacuum to expel ethyl acetate andproduce 360 mg of the captioned compound (yield 98.6%).

IR (Liquid film method) cm⁻¹ : 3340, 2942, 1607, 1580, 1241, 1075, 1052,731

EI - MS (m/z): 315 (M⁺), 314

NMR (CDCl₃) 400 MHz δ: 0.04-0.09 (2H, m), 0.44-0.50 (2H, m), 0.83 (1H,m), 1.36-1.42 (2H, m), 1.64-1.86 (4H, m) 1.93-2.28 (6H, m), 2.39 (1H,m), 2.68 (1H, t, J=12.0 Hz), 2.76 (1H, d, J=11.2 Hz), 2.92 (1H, m), 3.31(1H, m), 3.80 (3H, s), 6.69 (1H, m), 7.01-7.05 (2H, m), 7.21 (1H, t,J=8.0 Hz)

REFERENTIAL EXAMPLE 62-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline35 ##STR54##

In an atmosphere of argon, 0.11 ml of oxalyl chloride was dissolved in 5ml of anhydrous dichloromethane and the produced solution was cooled to-55° C. The cooled solution and a solution of 0.20 ml of DMSO in 0.5 mlof anhydrous dichloromethane added dropwise thereto were stirred at -55°C. for five minutes. The resultant mixture and a solution of 360 mg of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6β-hydroxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinein 2 ml of anhydrous dichloromethane added dropwise thereto were stirredat -55° C. for 15 minutes. The produced mixture and 1.0 ml oftriethylamine added dropwise thereto were heated to room temperature.The resultant reaction solution was combined with 5 ml of water andseparated in two layers. The organic layer consequently obtained waswashed with a saturated aqueous saline solution, dried, andconcentrated, to afford 330 mg of an oily substance. When this oilysubstance was separated and refined by column chromatography [silicagel; chloroform/methanol/28% aqua ammonia (98/2/0.1)], 290 mg of thecaptioned compound (yield 81.1%) was obtained.

By the procedure of Referential Examples 4 to 6, from 1.21 g of amixture of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6α-acetoxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinewith2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6β-acetoxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline,480 mg of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced (yield 60.6%).

IR (Liquid film method) cm⁻¹ : 2942, 1715, 1582, 1245, 1050, 754

EI - MS (m/z): 313 (M⁺)

NMR (CDCl₃) 400 MHz δ: 0.06-0.12 (2H, m), 0.46-0.54 (2H, m), 0.87 (1H,m), 1.94-2.11 (4H, m), 2.24-2.54 (7H, m), 2.68 (1H, t, J=11.7 Hz), 2.84(1H, m), 2.92 (1H, m), 3.05 (1H, m), 3.78 (3H, s), 6.69 (1H, m)6.97-7.00 (2H, m), 7.21 (1H, t, J=8.3 Hz)

By the procedure of Referential Examples 4 to 6,2-allyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using acryloyl chloride instead of cyclopropanecarbonylchloride,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using benzoyl chloride instead, and2-phenethyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineis produced by using phenylacetyl chloride instead.

EXAMPLE 312-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline36 ##STR55##

In an atmosphere of argon, 320 mg of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 195 mg of 4-fluorophenyl hydrazine hydrochloride were dissolved in10 ml of ethanol and the produced solution was heated to 80° C. Thissolution and 0.65 ml of methanesulfonic acid added thereto were stirredat 80° C. for 15 minutes and then cooled to room temperature. Theresultant mixture was distilled under a vacuum to expel ethanol,alkalinized by addition of an aqueous 1N sodium hydroxide solution, andextracted three times from 30 ml of chloroform. The organic layersconsequently separated were combined, washed with a saturated aqueoussaline solution, dried, and concentrated, to afford 370 mg of a powder.When this powder was separated and refined by column chromatography[silica gel; chloroform/methanol (97/3)], 360 mg of the captionedcompound (yield 87.2%) was obtained.

IR (Liquid film method) cm⁻¹ : 2898, 1607, 1580, 1489, 1460, 1294, 1238,1044

EI - MS (m/z): 404 (M⁺), 242, 161

NMR (CDCl₃) 400 MHz δ: 0.05-0.14 (2H, m), 0.47-0.56 (2H, m), 0.90 (1H,m), 1.95-2.07 (2H, m), 2.22-2.32 (2H, m), 2.39 (1H, m), 2.53-2.64 (2H,m), 2.87-2.99 (4H, m), 3.06 (1H, d, J=16.1 Hz), 3.15 (1H, d, J=8.8 Hz),3.68 (3H, s), 6.62 (1H, m), 6.80 (1H, td, 9.0 Hz, 2.4 Hz), 7.00-7.11(5H, m), 7.58 (1H, brs)

Similarly,2-cyclopropylmethyl-4aα-3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using phenyl hydrazine instead of4-fluorophenylhydrazine,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-fluorophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-fluorophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-methylphenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-methylphenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline isproduced by using 2-methylphenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-chlorophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-chlorophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-chlorophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-bromophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-bromophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-bromophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-nitrophenylhydrazine instead,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-nitrophenylhydrazine,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-nitro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 2-nitrophenylhydrazine instead, and2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6-methyl-indolo[2,3-g]isoquinolineis produced by using 1-methyl-1-phenyl hydrazine instead.

EXAMPLE 322-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline37 ##STR56##

In an atmosphere of argon, 250 mg of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinewas dissolved in 6 ml of anhydrous DMF and the produced solution and 350mg of potassium-t-butoxide and 0.31 ml of n-propane thiol added theretowere stirred at 150° C. for three hours. The resultant mixture wascooled to room temperature, distilled under a vacuum to expel DMF,combined with 10 ml of water, and extracted three times from 30 ml ofchloroform/methanol (3/1). The organic layers consequently separatedwere combined, washed with a saturated aqueous saline solution, dried,and concentrated to afford 220 mg of a powder. This powder was suspendedin 2 ml of methanol, converted into a methanesulfonate by addition of 40μl of methanesulfonic acid, and separated and refined by columnchromatography [Sephadex; LH-20; methanol], to produce 199 mg of themethanesulfonate of the captioned compound (decomposed at 245° C.)(yield 66.2%).

IR (KBr) cm⁻¹ : 3392, 1586, 1477, 1249, 1173, 1049, 790

FAB - MS (m/z): 391 (M⁺ +1)

NMR (DMSO-d₆) 500 MHz δ: 0.35-0.41 (2H, m), 0.61-0.65 (2H, m), 1.07 (1H,m), 2.07 (1H, m), 2.31 (3H, s), 2.53-2.67 (3H, m) 2.87-3.06 (5H, m),3.12 (1H, d, J=16.5 Hz), 3.48 (1H, m), 3.51 (1H, m), 3.72 (1H, m), 6.54(1H, m), 6.80 (1H, td, J=9.2 Hz, 2.4 Hz), 6.92 (1H, brs), 6.93 (1H, brd,J=8.6 Hz), 7.04 (1H, t, J=7.9 Hz), 7.09 (1H, dd, J=9.8 Hz, 2.4 Hz), 7.17(1H, dd, J=8.5 Hz, 4.3 Hz), 9.26 (1H, s), 9.40 (1H, brs), 10.73 (1H, s)

Elementary analyses

    ______________________________________                                        For C.sub.25 H.sub.27 N.sub.2 OF.CH.sub.3 SO.sub.3 H                                  C       H      N         F    S                                       ______________________________________                                        Calculated                                                                              64.18     6.42   5.76    3.90 6.59                                  Found     63.91     6.61   5.91    3.91 6.57                                  ______________________________________                                    

EXAMPLE 332-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline38 ##STR57##

In an atmosphere of argon, 520 mg of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 360 mg of 2-chlorophenyl hydrazine sulfate were dissolved in 10 mlof ethanol and the produced solution was heated to 80° C. The resultantmixture and 1.0 ml of methanesulfonic acid added thereto were stirred at80° C. for 15 minutes and then cooled to room temperature. By separatingthe precipitated crystals through filtration, 480 mg of the captionedcompound (yield 66.1%) was obtained.

IR (KBr) cm⁻¹ : 3284, 1615, 1578, 1493, 1460, 1257, 1234, 1052, 878, 775

EI - MS (m/z): 434 (M⁺), 432, 177

NMR (CDCl₃) 400 MHz δ: 0.75-0.80 (2H, m), 0.96-1.05 (2H, m), 1.74-1.88(2H, m), 2.34-2.49 (2H, m), 2.75-2.99 (4H, m), 3.10-3.28 (2H, m), 3.70(3H, s), 4.04-4.75 (2H, brm), 6.67 (1H, m), 6.97-7.05 (3H, m), 7.08 (1H,brd, J=7.9 Hz), 7.14 (1H, t, J=7.9 Hz), 7.33 (1H, d, J=7.6 Hz), 7.85(1H, brs)

Similarly,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using 4-chlorophenyl hydrazine instead of 2cyclophenylhydrazine, and2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineand2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-chlorophenyl hydrazine instead.

EXAMPLE 342-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline39 ##STR58##

In an atmosphere of argon, 110 mg of lithium aluminum hydride wassuspended in 10 ml of anhydrous THF and the suspension was cooled to 0°C. This suspension and a suspension of 400 mg of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinein 10 ml of anhydrous THF added dropwise thereto were heated to roomtemperature and stirred for two hours. The resultant mixture was cooledto 0° C. and combined with ethyl acetate and a saturated aqueoussolution of potassium sodium tartrate. The produced mixture was filteredto remove insolubles and distilled under a vacuum to expel ethyl acetateand produce 440 mg of an oily substance. When this oily substance wasseparated and refined by column chromatography [silica gel;chloroform/methanol (98/2)], there were obtained 390 mg of crudecrystals. When these crude crystals were recrystallized from ethylacetate, 256 mg of the captioned compound in a purified form (m.p. 96°to 98° C.) (yield 66.1%) was obtained.

IR (KBr) cm⁻¹ : 2906, 1607, 1578, 1491, 1460, 1243, 1052, 777

EI - MS (m/z): 420 (M⁺), 422, 242

NMR (CDCl₃) 500 MHz δ: 0.08-0.24 (2H, m), 0.50-0.56 (2H, m), 0.90 (1H,m), 1.99-2.08 (2H, m), 2.24-2.34 (2H, m), 2.41 (1H, m), 2.57-2.67 (2H,m), 2.91-3.03 (4H, m), 3.13 (1H, d, J=15.9 Hz), 3.17 (1H, brd, J=9.2Hz), 3.69 (3H, s), 6.62 (1H, m), 6.98 (1H, t, J=7.9 Hz), 7.01-7.07 (3H,m), 7.10 (1H, t, J=7.9 Hz), 7.32 (1H, d, J=7.9 Hz), 7.81 (1H, brs)

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropyl-carbonyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-chloropropylcarbonyl-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead.

EXAMPLE 352-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline40 ##STR59##

In an atmosphere of argon, 270 mg of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolinewas dissolved in 6 ml of anhydrous DMF and the produced solution and 400mg of potassium-t-butoxide and 0.36 ml of n-propane thiol added theretowere stirred at 150° C. for 2.5 hours. The resultant mixture was cooledto room temperature, distilled under a vacuum to expel DMF, combinedwith 5 ml of water, and extracted from 30 ml of chloroform/methanol(3/1). The organic layers consequently separated were combined, washedwith a saturated aqueous saline solution, dried, and concentrated toafford 230 mg of a powder. When this powder was suspended in 2 ml ofmethanol, converted into a methanesulfonate by addition of 40 μl ofmethanesulfonic acid, and separated and refined by column chromatography[Sephadex; LH-20; methanol], 260 mg of crude crystals were obtained.When the crude crystals were recrystallized from methanol, 149 mg of themethanesulfonate of the captioned compound (decomposed at 260° C.)(yield 46.2%) was obtained.

IR (KBr) cm⁻¹ : 3320, 1599, 1460, 1201, 1164, 1042, 772

FAB - MS (m/z): 407 (M⁺ +1)

NMR (DMSO-d₆) 400 MHz δ: 0.35-0.40 (2H, m), 0.61-0.66 (2H, m), 1.06 (1H,m), 2.06 (1H, m), 2.30 (3H, s), 2.54-2.68 (3H, m), 2.86-3.06 (5H, m),3.20 (1H, brd, J=16.1 Hz), 3.37 (1H, m), 3.52 (1H, m), 3.73 (1H, m),6.54 (1H, m), 6.88 (1H, m), 6.92-6.97 (2H, m), 7.02-7.07 (2H, m), 7.33(1H, d, J=7.8 Hz), 9.27 (1H, s), 9.38 (1H, brs), 10.97 (1H, s)

Elementary analyses

    ______________________________________                                        For C.sub.25 H.sub.27 N.sub.2 OCl.CH.sub.3 SO.sub.3 H.0.2H.sub.2 O                    C       H      N         Cl   S                                       ______________________________________                                        Calculated                                                                              61.64     6.25   5.53    7.00 6.33                                  Found     61.46     6.25   5.56    7.14 6.26                                  ______________________________________                                    

Similarly,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-cyclopropylmethy-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineinstead, and2-cyclopropylmethy-4aα-(3-hydroxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinolineis produced by using2-cyclopropylmethy-4aα-(3-methoxyphenyl)-10-chloro-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline.

REFERENTIAL EXAMPLE 7 Optical resolution of(±)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,11,11a.beta.-decahydroisoquinolinewith (+)-di-(p-toluoyl)-D-tartaric acid and(-)-di-(p-toluoyl)-L-tartaric acid 41 42

In methanol, 3.13 g of(±)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,11,11a.beta.-decahydroisoquinolineand 4.68 g of (+)-di-(p-toluoyl)-D-tartaric acid were dissolved. Theproduced solution was concentrated and crystallized. the resultant saltwas dissolved by heating in methanol. In the solution, seeds of(-)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,11,11aβ-decahydroisoquinoline·(+)-di-(p-toluoyl)-D-tartratewere left standing at room temperature for a whole day and night. Thecrystals consequently educed in the solution were separated byfiltration and the separated crystals were separated by filtration andthe separated crystals were repetitively recrystallized in the samemanner as above, to obtain 1.65 g of crystals. These salt crystals weresuspended in 15 ml of 1N sodium hydroxide and extracted two times from25 ml of ethyl acetate. The organic layers consequently separated werewashed with a saturated aqueous solution of sodium chloride, dried withanhydrous sodium sulfate, and concentrated, to afford 0.68 g of(-)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,11,11aβ-decahydroisoquinoline(yield 43.5%). The crude crystals, on being recrystallized (ethylacetate/n-hexane), produced 0.45 g of needle crystals (m.p. 91.3° to91.8° C.).

Then, 4.28 g of the concentrate of the mother liquor produced by theresolution described above was suspended in 40 ml of 1N sodium hydroxideand extracted two times from 50 ml of ethyl acetate. The organic layersconsequently separated were washed with a saturated aqueous solution ofsodium chloride, dried with anhydrous sodium sulfate, and thenconcentrated, to afford 2.21 g of(±)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a.beta.-decahydroisoquinolineand 3.12 g of (-)-di-(p-toluoyl)-L-tartaric acid. These compounds weredissolved in methanol, concentrated, and then crystallized. Theresultant salt was dissolved by heating in methanol. In the solution,seeds of(+)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline·(-)-di-(p-toluoyl)-L-tartratewere left standing at room temperature for a whole day and night. Thecrystals consequently educed in the solution were separated byfiltration, to afford 2.16 g of crystals. The salt crystals weresuspended in 20 ml of 1N sodium hydroxide and extracted two times from30 ml of ethyl acetate. The organic layers consequently separated werewashed with a saturated aqueous solution of sodium chloride, dried withanhydrous sodium sulfate, and then concentrated, to form 0.89 g of(+)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline(yield 56.8%). The crude crystals, on being recrystallized from ethylacetate/n-hexane, there were produced 0.60 g of needle crystals (m.p.91.0 ° to 91.5° C.).

(-)-2-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a.beta.-decahydroisoquinoline

[α]²⁰ _(D) =-67° (C=2.0, MeOH)

IR (KBr) cm⁻¹ : 2944, 2908, 2850, 2798, 1709, 1605, 1578

NMR (CDCl₃) 500 MHz δ: 1.88-2.00 (3H, m), 2.08 (1H, m), 2.32 (3H, s),2.31-2.50 (5H, m), 2.60 (1H, m), 2.69 (1H, t, J=11.6 Hz), 2.84 (1H, dd,J=11.6 Hz, J=3.1 Hz), 2.93 (1H, dd, J=14.0 Hz, J=1.2 Hz), 3.78 (3H, s),6.71 (1H, m), 6.97-7.00 (2H, m), 7.21 (1H, m)

Mass (m/e): 273 (M⁺)

(+)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline

[α]²⁰ _(D) =+66° (C=2.0, MeOH)

IR (KBr) cm⁻¹ : 2946, 2908, 2844, 2798, 1709, 1605, 1578

NMR (CDCl₃) 400 MHz δ: 1.88-2.00 (3H, m), 2.07 (1H, m), 2.32 (3H, s),2.31-2.50 (5H, m), 2.60 (1H, m), 2.69 (1H, t, J=11.7 Hz), 2.84 (1H, m),2.93 (1H, d, J=14.2 Hz), 3.78 (3H, s), 6.71 (1H, m), 6.97-7.00 (2H, m),7.21 (1H, m)

Mass (m/e): 273 (M⁺)

REFERENTIAL EXAMPLE 8(-)-2-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline43

In an atmosphere of argon, 598 mg of proton sponge was dissolved in 15ml of anhydrous methylene chloride and 0.433 ml of2,2,2-trichloroethoxycarbonyl chloride was added dropwise thereto in astirred state. Then, the resultant mixture was kept cooled with ice anda solution of 507 mg of(-)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinein 5 ml of anhydrous methylene chloride was added dropwise theretomeantimes. The produced mixture was returned to room temperature andstirred continuously for two hours. The resultant reaction solution wasconcentrated, then redissolved in 20 ml of ethyl acetate, washed with 10ml 1N hydrochloride acid, 10 ml of water, and 10 ml of a saturatedaqueous solution of sodium chloride, dried with anhydrous sodiumsulfate, and concentrated, to afford 1.41 g of an oily substance. Whenthis oily substance was separated and refined by column chromatography[silica gel; cyclohexane/ethyl acetate (1/1)], 806 mg of the captionedcompound (yield 100%) was obtained.

IR (liquid film method) cm⁻¹ : 2958, 1715, 1607, 1582

NMR (CDCl₃) 500 MHz δ: 1.80 (1H, m), 2.03 (1H, m), 2.13 (1H, m), 2.25(1H, m), 2.31-2.44 (4H, m), 2.85 (1H, m), 2.96 (1H, d, J=14.0 Hz), 3.53(1H, m), 3.78 (3H, s), 4.03 (1H, m), 4.18 (1H, m), 4.71-4.81 (2H, m),6.75 (1H, m), 6.95-6.98 (2H, m), 7.25 (1H, m)

Mass (m/e): 433 (M⁺)

REFERENTIAL EXAMPLE 9(-)-2-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline44

A solution of 800 mg of(-)-2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinein 20 ml of acetic acid and 1.2 g of zinc powder added thereto werestirred at room temperature for 3.5 hours. The resultant reactionmixture was filtered with a filter cell to remove zinc and washed threetimes with 20 ml of acetic acid. The washed mixture was concentrated,alkalinized by addition of a saturated aqueous solution of sodiumhydrogen carbonate, and extracted three times from 40 ml of chloroform.The organic layers consequently separated were washed with a saturatedaqueous solution of sodium chloride, dried with anhydrous sodiumsulfate, and concentrated to afford 524 mg of an oily substance.

Subsequently, this oily substance was subjected to azeotropicdistillation two times with 10 ml of benzene. In an atmosphere of argon,the resultant azeotropic mixture was dissolved in 18 ml of anhydrousmethylene chloride and combined with 0.513 ml of anhydrous triethylamineand the produced mixture and 0.267 ml of cyclopropanecarbonyl chlorideadded dropwise thereto at room temperature was continuously stirred forfour hours. The resultant mixture was deprived of methylene chloride andredissolved in 20 ml of ethyl acetate. The produced solution was washedwith 1N HC1 and a saturated aqueous solution of sodium chloride, driedwith anhydrous sodium sulfate, and concentrated, to afford 641 mg of anoily substance. When this oily substance was separated and refined bycolumn chromatography [silica gel: cyclohexane/ethyl (3/1)], 345 mg ofthe captioned compound (yield 57.4%) was obtained.

m.p.=149° to 150° C. (recrystallized with n-hexane/ethyl acetate)

[α]²⁰ _(D) =-107° (C=1.0, CHCl₃)

IR (KBr) cm⁻¹ : 2934, 2872, 1715, 1624, 1599

NMR (CDCl₃) 400 MHz δ: 0.76-0.79 (2H, m), 0.91-1.00 (2H, m), 1.59 (1H,s), 1.74-1.84 (2H, m), 2.03 (1H, m), 2.16 (1H, d, J=13.7 Hz), 2.25 (1H,m), 2.38-2.42 (3.5H, m), 2.76 (0.5 H, m), 2.97 (1H, d, J=14.2 Hz), 3.07(0.5 H, m), 3.27 (0.5 H, m), 3.79 (3H, s), 4.01 (0.5 H, m), 4.12 (0.5 H,m), 4.33 (0.5 H, m), 4.59 (0.5 H, m), 6.75 (1H, dd, J=8.3 HZ, J=2.4 Hz),6.95-7.01 (2H, m), 7.25 (1H, m)

Mass (m/e): 327 (M⁺)

EXAMPLE 36(+)-2-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline45

In 4 ml of ethanol, 340 mg of (-)-2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 0.113 ml of phenyl hydrazine were dissolved. The solution keptrefluxed thermally and 0.675 ml of methanesulfonic acid added theretomeanwhile were stirred and further refluxed continuously for 0.5 hour.The resultant reaction mixture was cooled to room temperature, keptcooled with ice, combined with 20 ml of a saturated aqueous solution ofsodium hydrogen carbonate, and extracted two times from 30 ml ofchloroform. The organic layers consequently separated were combined,washed with a saturated aqueous solution of sodium chloride, dried withanhydrous sodium sulfate, and then concentrated, to afford 507 mg of anoily substance. When this oily substance was separated and refined bycolumn chromatography [silica gel; chloroform], 354 mg of the captionedcompound (yield 85.0%) was obtained.

IR (KBr) cm⁻¹ : 3204, 2902, 1607, 1460

NMR (CDCl₃) 500 MHz δ: 0.75-0.78 (2H, m), 0.92-1.00 (2H, m), 1.58 (1H,s), 1.75-1.90 (2H, m), 2.37-2.48 (2H, m), 2.89 (1H, d, J=15.9 Hz),2.95-3.02 (2H, m), 3.13 (1H, d, J=15.9 Hz), 3.19 (1H, m), 3.68 (3H, s),4.08 (0.5 H, d, J=13.4 Hz), 4.22 (0.5 H, d, J=9.2 Hz), 4.44 (0.5 H, d,J=13.4 Hz), 4.69 (0.5 H, d, J=9.2 Hz), 6.65 (1H, m), 7.00-7.14 (5H, m),7.22 (1H, m), 7.44 (1H, d, J=7.3 Hz), 7.60 (0.5 H, s), 7.67 (0.5 H, s)

Mass (m/e): 400 (M⁺)

EXAMPLE 37(+)-2-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline46

In an atmosphere or argon, 100 mg of lithium aluminum hydride wassuspended in 8 ml of anhydrous THF. To the produced suspension, asolution of 345 mg of(+)-2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolinein 17 ml of anhydrous THF was added dropwise as kept cooled with ice.Then, the resultant mixture was stirred at room temperature for twohours. To the resultant reaction mixture, ethyl acetate and a saturatedaqueous solution of potassium sodium tartrate were alternately addeddropwise and quenched. The mixture was filtered with a filtration cellto remove insolubles and washed three times with 20 ml of ethyl acetate.The mother liquors consequently separated were combined andconcentrated, to obtain 318 mg of a powder. When this powder wasseparated and refined by column chromatography [silica gel;chloroform/methanel (19/1)], 295 mg of the captioned compound (yield88.7%) was obtained.

m.p.=194.2° to 194.6° C. (recrystallized from ethyl acetate/ethanol)

[α]²⁰ _(D) =+151° (C=1.0, CHCl₃)

IR (KBr) cm⁻¹ : 2932, 2838, 1607, 1580, 1454

NMR (CDCl₃) 400 MHz δ: 0.08-0.12 (2H, m), 0.48-0.56 (2H, m), 0.89 (1H,m), 1.99-2.08 (2H, m), 2.22-2.33 (2H, m), 2.40 (1H, m), 2.58-2.64 (2H,m), 2.88-3.00 (4H, m), 3.07 (1H, d, J=16.1 Hz), 3.16 (1H, d, J=6.8 Hz),3.67 (3H, s), 6.60 (1H, m), 7.02-7.10 (5H, m), 7.20 (1H, m), 7.44 (1H,m), 7.59 (1H, s)

Mass (m/e): 386 (M⁺)

EXAMPLE 38(+)-2-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline47

In an atmosphere of argon, 285 mg of(+)-2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineand 497 mg of potassium-t-butoxide were dissolved in 7 ml of anhydrousDMF and the produced solution was combined with 0.415 ml of 1-propanethiol. The resultant mixture was stirred at 140° C. for 3.5 hours andthen cooled to room temperature. The mixture was distilled under avacuum to expel DMF, combined with 20 ml of a saturated aqueous solutionof sodium hydrogen carbonate, and extracted three times from 40 ml of amixed solvent of chloroform: methanol (3:1). The organic layersconsequently separated were combined, washed with a saturated aqueoussolution of sodium chloride, dried with anhydrous magnesium sulfate, andthen concentrated, to afford 337 mg of a powder. When this powder wassuspended in 2 ml of methanol, converted into a methanesulfonate byaddition of methanesulfonic acid, and then separated by columnchromatography (Sephadex, LH-20; methanol), 208 mg of themethanesulfonate of the captioned compound (yield 60.3%), d.p.=240° C.minimum (recrystallized from methanol) was obtained.

[α]²⁰ _(D) =+45° (C=0.19, DMF)

IR (KBr) cm⁻¹ : 3402, 2718, 1599, 1444

NMR (DMSO) 500 MHz δ: 0.37-0.38 (2H, m), 0.63-0.67 (2H, m), 1.06 (1H,m), 2.08 (1H, m), 2.31 (3H, s), 2.55-2.64 (2H, m), 2.88-2.94 (2H, m),2.97-3.07 (3H, m), 3.09 (1H, d, J=11.0 Hz), 3.33-3.46 (2H, m), 3.52 (1H,d, J=12.8 Hz), 3.74 (1H, d, J=11.0 Hz), 6.53 (1H, dd, J=7.9 Hz, J=1.8Hz), 6.90-6.99 (4H, m), 7.04 (1H, t, J=7.9 Hz), 7.19 (1H, d, J=7.9 Hz),7.34 (1H, d, J=7.3 Hz), 9.25 (1H, s), 9.39 (1H, brs), 10.61 (1H, s)

Mass (FAB): 373 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.25 H.sub.28 N.sub.2 O.CH.sub.3 SO.sub.3 H                                     C    H           N      S                                           ______________________________________                                        Calculated  66.64  6.88        5.98 6.84                                      Found       66.45  6.96        5.90 6.80                                      ______________________________________                                    

REFERENTIAL EXAMPLE 10(+)-2-(2,2,2-Trichloroethoxycarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline48

In an atmosphere of argon, 601 mg of proton sponge was dissolved in 15ml of anhydrous methylene chloride and 0.435 ml of2,2,2-trichloroethoxycarbonyl chloride was added dropwise to theproduced solution as kept in a stirred state. The resultant mixture waskept cooled with ice and a solution of 509 mg of(+)-2-methyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinein 5 ml of anhydrous methylene chloride was added dropwise thereto.Then, the produced mixture was returned to room temperature and stirredcontinuously for 1.5 hours. The reaction solution consequently formedwas concentrated, redissolved in 20 ml of ethyl acetate, washed with 5ml of 1N hydrochloric acid, 5 ml of water, and 10 ml of a saturatedaqueous solution of sodium chloride, dried with anhydrous sodiumsulfate, and then concentrated, to afford 1.09 g of an oily substance.When this oily substance was separated and refined by columnchromatography [silica gel; cyclohexane/ethyl acetate (1/1)], 810 mg ofthe captioned compound (yield 100%) was obtained.

IR (liquid film method) cm⁻¹ : 2990, 1713, 1607, 1582

NMR (CDCl₃) 400 MHz δ: 1.80 (1H, m), 2.03 (1H, m), 2.13 (1H, m), 2.25(1H, m), 2.31-2.44 (4H, m), 2.85 (1H, m), 2.96 (1H, d, J=14.2 Hz), 3.53(1H, m), 3.78 (3H, s), 4.02 (1H, m), 4.18 (1H, m), 4.71-4.81 (2H, m),6.75 (1H, m), 6.95-6.98 (2H, m), 7.25 (1H, m)

Mass (m/e): 433 (M⁺)

REFERENTIAL EXAMPLE 11(+)-2-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinoline49

A solution of 800 mg of(+)-2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolinein 20 ml of acetic acid and 1.2 g of zinc powder added thereto werestirred at room temperature for four hours. Then, the resultant reactionmixture was filtered with a filter cell to remove zinc and washed threetimes with 20 ml of acetic acid. The washed residue of filtration wasconcentrated, then alkalinized by addition of a saturated aqueoussolution of sodium hydrogen carbonate, and extracted three times from 40ml of chloroform. The organic layers consequently separated were washedwith a saturated aqueous solution of sodium chloride, dried withanhydrous sodium sulfate, and then concentrated, to afford 520 mg of anoily substance.

Subsequently, this oily substance was subjected two times to azeotropicdistillation with 10 ml of benzene. In an atmosphere of argon, theresultant azeotropic mixture was dissolved in 18 ml of anhydrousmethylene chloride, combined with 0.513 ml of anhydrous triethylamine.At room temperature, the resultant mixture and 0.267 ml ofcyclopropanecarbonyl chloride added dropwise thereto were stirredcontinuously for four hours. Then, the mixture was deprived of methylenechloride and the residue was redissolved in 20 ml of ethyl acetate. Theproduced solution was washed with 1N HC1 and a saturated aqueoussolution of sodium chloride, dried with anhydrous sodium sulfate, andconcentrated, to afford 427 mg of an oily substance. When this oilysubstance was separated and refined by column chromatography [silicagel; cyclohexane/ethyl acetate (3/1)], 292 mg of the captioned compound(yield 48.6%) was obtained.

m.p.=150° to 151° C. (recrystallized from ethyl acetate)

[α]²⁰ _(D) =+110° (C=1.0, CHCl₃)

IR (KBr) cm⁻¹ : 2934, 2872, 1715, 1624, 1599

NMR (CDCl₃) 400 MHz δ: 0.76-0.79 (2H, m), 0.91-1.00 (2H, m), 1.59 (1H,s), 1.74-1.84 (2H, m), 2.03 (1H, m), 2.16 (1H, d, J=13.7 Hz), 2.25 (1H,m), 2.38-2.42 (3.5 H, m), 2.76 (0.5 H, m), 2.97 (1H, d, J=14.2 Hz), 3.07(0.5 H, m), 3.27 (0.5 H, m), 3.79 (3H, s), 4.01 (0.5 H, m), 4.12 (0.5 H,m), 4.33 (0.5 H, m), 4.59 (0.5 H, m), 6.75 (1H, dd, J=8.3 Hz, J=2.4 Hz),6.95-7.01 (2H, m), 7.25 (1H, m)

Mass (m/e): 327 (M⁺)

EXAMPLE 39(-)-2-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline50

In 2 ml of ethanol, 145 mg of(+)-2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8aβ-decahydroisoquinolineand 0.048 ml of phenyl hydrazine were dissolved. The produced solutionkept refluxed thermally and 0.288 ml of methanesulfonic acid addedthereto meanwhile were stirred and further refluxed for 0.5 hourcontinuously. The resultant reaction mixture was cooled to roomtemperature, combined with 15 ml of a saturated aqueous solution ofsodium hydrogen carbonate as kept cooled with ice, and extracted twotimes from 30 ml of chloroform. The organic layers consequentlyseparated were combined, washed with a saturated aqueous solution ofsodium chloride, dried with anhydrous sodium sulfate, and thenconcentrated, to afford 194 mg of an oily substance. When this oilysubstance was separated and refined by column chromatography [silicagel; chloroform], 160 mg of the captioned compound (yield 90.3%) wasobtained.

IR (KBr) cm⁻¹ : 3204, 2902, 1607, 1460

NMR (CDCl₃) 400 MHz δ: 0.75-0.78 (2H, m) 0.92-1.00 (2H, m), 1.58 (1H,s), 1.75-1.90 (2H, m), 2.37-2.48 (2H, m), 2.88-3.02 (3H, m), 3.12-3.30(2H, m), 3.68 (3H, s), 4.08-4.69 (2H, m), 6.65 (1H, m), 7.00-7.14 (5H,m), 7.22 (1H, m), 7.44 (1H, m), 7.63 (1H, brs)

Mass (m/e): 400 (M⁺)

EXAMPLE 40(-)-2-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline51

In an atmosphere of argon, 44 mg of lithium aluminum hydride wassuspended in 3 ml of anhydrous THF and a solution of 150 mg of(-)-2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolinein 7 ml of anhydrous THF was added dropwise to the suspension keptcooled with ice. The resultant mixture was stirred at room temperaturefor one hour. The resultant reaction mixture was kept cooled with iceand ethyl acetate and a saturated aqueous solution of potassium sodiumtartrate were alternately added dropwise thereto meanwhile and theproduced mixture was quenched. The mixture was filtered with afiltration cell to remove insolubles and the residue of the filtrationwas washed three times with 20 ml of ethyl acetate. The mother liquidsconsequently separated were combined and concentrated, to afford 141 mgof a powder. When this powder was separated and refined by columnchromatography [silica gel; chloroform/methanol (9/1)], 132 mg of thecaptioned compound (yield 91.2%) was obtained.

m.p.=195.0° to 195.3° C. (recrystallized from ethyl acetate)

[α]²⁰ _(D) =-137° (C=1.0, CHCl₃)

IR(KBr)cm⁻¹ : 2930, 2838, 1607, 1578, 1454

NMR (CDCl₃) 400 MHz δ: 0.08-0.12 (2H, m), 0.48-0.56 (2H, m), 0.89 (1H,m), 1.99-2.08 (2H, m), 2.24-2.35 (2H, m), 2.40 (1H, m), 2.58-2.66 (2H,m), 2.89-3.00 (4H, m), 3.07 (1H, d, J=15.6 Hz), 3.17 (1H, d, J=7.8 Hz),3.67 (3H, s), 6.60 (1H, m), 7.02-7.10 (5H, m), 7.20 (1H, m), 7.44 (1H,m), 7.59 (1H, s)

Mass (m/e): 386 (M⁺)

EXAMPLE 41(-)-2-Cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinoline52

In an atmosphere of argon, 127 mg of(-)-2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11a.beta.-octahydro-6H-indolo[2,3-g]isoquinolineand 221 mg of potassium-t-butoxide were dissolved in 3 ml of anhydrousDMF and 0.185 ml of 1-propane thiol was added to the produced solution.The mixture was stirred at 140° C. for three hours and then cooled toroom temperature. This mixture was distilled under a vacuum to expelDMF, combined with 10 ml of a saturated aqueous solution of sodiumhydrogen carbonate, and extracted three times from 20 ml of a mixedsolvent of chloroform: methanol (3:1). The organic layers consequentlyseparated were combined, washed with a saturated aqueous solution ofsodium chloride, dried with anhydrous magnesium sulfate, and thenconcentrated, to afford 150 mg of a powder. When this powder wassuspended in 1 ml of methanol, converted into a methane-sulfonate byaddition of methanesulfonic acid, and then separated and refined bycolumn chromatography [Sephadex, LH-20; methanol], 54 mg of themethanesulfonate of the optioned compound (yield 35.1%) was obtained.

d.p.=240° C. minimum (recrystallized from methanol)

[α]²⁰ _(D) =-48° (C=0.21, DMF)

IR (KBr) cm⁻¹ : 3404, 2710, 1601, 1444

NMR (DMSO) 500 MHz δ: 0.37-0.38 (2H, m), 0.63-0.66 (2H, m), 1.06 (1H,m), 2.08 (1H, m), 2.31 (3H, s), 2.55-2.64 (2H, m), 2.88-2.94 (2H, m),2.97-3.07 (3H, m), 3.12 (1H, d, J=16.5 Hz), 3.33-3.46 (2H, m), 3.51 (1H,d, J=11.0 Hz), 3.73 (1H, d, J=11.6 Hz), 6.53 (1H, d, J=7.9 Hz),6.90-6.99 (4H, m), 7.03 (1H, t, J=7.9 Hz), 7.19 (1H, d, J=7.9 Hz), 7.34(1H, d, J=7.3 Hz), 9.24 (1H, s), 9.38 (1H, brs), 10.61 (1H, s)

Mass (FAB): 373 (M⁺ +1)

Elementary analyses

    ______________________________________                                        For C.sub.25 H.sub.28 N.sub.2 O.CH.sub.3 SO.sub.3 H.0.6H.sub.2 O                        C    H           N      S                                           ______________________________________                                        Calculated  65.14  6.98        5.84 6.69                                      Found       65.22  6.83        5.75 6.67                                      ______________________________________                                    

The (+) forms and (-) forms of the compounds described hereinabove canbe produced by following the pertinent procedures of ReferentialExamples 7, 8, 9, 10, and 11 and Examples 36, 37, 38, 39, 40, and 41.

EXAMPLE 422-Methyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline53 ##STR60##

In 3 ml of ethanol, 102 mg (0.35 mmol) of2-methyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinewas dissolved. To the produced solution was added 38.2 μl (0.39 mmol) ofphenyl hydrazine. The mixture was heated to 80° C. and allowed to reactwith 228 μl (3.5 mmol) of methanesulfonic acid at the same temperaturefor two hours. The reaction mixture was left cooling to roomtemperature, then poured in 20 ml of a saturated aqueous solution ofsodium hydrogen carbonate, and extracted two times from 15 ml ofchloroform. The extract was washed with 10 ml of a saturated aqueoussaline solution, dried, concentrated, and refined by silica gel columnchromatography [7734, 8 g; chloroform to chloroform/ammonia-saturatedchloroform (3/1)], to afford the captioned compound (114%, inclusive ofthe solvent).

IR (KBr) cm⁻¹ : 3304, 2918, 1605, 1580, 1464, 1236, 1040, 785, 741

NMR (CDCl₃) 500 MHz δ: 2.20-2.30 (2H, m), 2.33 (3H, s), 2.40 (1H, dt,J=12.8, 4.3 Hz), 2.66 (2H, s), 2.70-2.75 (1H, m), 2.79 (1H, d, J=15.9Hz), 2.92 (1H, d, J=15.3 Hz), 3.22 (1H, t, J=15.9 Hz), 3.64 (3H, s),6.63 (1H, dt, J=6.7, 1.8 Hz), 7.04-7.20 (5H, m), 7.20 (1H, dd, J=6.7,1.8 Hz), 7.44 (1H, d, J=6.7 Hz), 7.62 (1H, brs)

Mass (EI): 362 (M⁺)

Similarly,2-methyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2 -methyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-methyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6-methyl-indro(2,3-g)isoquinolineare produced by using p-tollyl hydrazine, m-tollyl hydrazine, o-tollylhydrazine, 4-chlorophenyl hydrazine, 3-chlorophenyl hydrazine,2-chlorophenyl hydrazine, 4-fluorophenyl hydrazine, 3-fluorophenylhydrazine, 2-fluorophenyl hydrazine, 4-bromophenyl hydrazine,3-bromophenyl hydrazine, 2-bromophenyl hydrazine, 4-nitrophenylhydrazine, 3-nitrophenyl hydrazine, 2-nitrophenyl hydrazine andphenylmethyl hydrazine respectively, instead of phenyl hydrazine.

EXAMPLE 432-Methyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline54 ##STR61##

The2-methyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineobtained as described above was dissolved in 5 ml of anhydrous DMF andcaused to react with 0.25 ml (2.8 mmol) of propane thiol and 220 mg (2.0mmol) of potassium-t-butoxide at 150° C. for three hours. The reactionmixture was distilled under a vacuum to expel the solvent, combined with10 ml of a saturated aqueous solution of sodium hydrogen carbonate, andextracted two times from 10 ml of ethanol/chloroform (3/1). The extractwas washed with a saturated aqueous saline solution, dried,concentrated, and refined by silica gel column chromatography (7734, 10g; chloroform-ammonia-saturated chloroform-5% methanol/ammonia-saturatedchloroform), to afford 55.6 mg of the captioned compound (45% in twosteps). This compound was dissolved in methanol and, by addition of 10.9μl of methanesulfonic acid, isolated in the form of a salt.

m.p.=189° to 192° C. (methanesulfonate, discolored to brown at 172° C.)

IR (KBr) cm⁻¹ : 3408, 2926, 1584, 1454, 1323, 1236, 1048, 897, 741

Mass (EI): 348 (M⁺)

Elementary analyses

    ______________________________________                                        For C.sub.22 H.sub.24 N.sub.2 O.sub.2 CH.sub.3 SO.sub.3 HH.sub.2 O                      C    H           N      S                                           ______________________________________                                        Calculated  59.72  6.54        6.05 6.93                                      Found       59.58  6.72        5.96 7.01                                      ______________________________________                                    

Similarly,2-methyl-4aα-(3-hydroxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo-[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-hydroxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-methyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using2-methyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-methyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6-methyl-indolo[2,3-g]isoquinolinerespectively instead of2-methyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline.

EXAMPLE 442-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline55 ##STR62##

In 3 ml of ethanol, 102 mg (0.31 mmol) of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinewas dissolved and the produced solution was combined with 34 μl (0.34mmol) of phenyl hydrazine. The resultant mixture was heated to 80° C.and then caused to react with 202 μl (3.1 mmol) of methanesulfonic acidat the same temperature for three hours. The reaction mixture was leftcooling to room temperature, poured into 12 ml of a saturated aqueoussolution of sodium hydrogen carbonate, and extracted two times from 10ml of chloroform. The extract was washed with 10 ml of a saturatedaqueous saline solution, dried, then concentrated, and refined by silicagel column chromatography (9385, 10 g; chloroform - 2%methanol/chloroform - 5% methanol/chloroform), to obtain 96.6 mg of thecaptioned compound (yield 77%).

IR (liquid film method) cm⁻¹ : 3302, 2914, 1605, 1580, 1456, 1236, 1040,874, 741

NMR (CDCl₃, 500 MHz) δ: 0.04-0.10 (2H, m), 0.45-0.53 (2H, m), 0.72-0.84(1H, m), 2.18-2.26 (2H, m), 2.36 (1H, s), 2.36 (1H, dt, J=12.4, 4.0 Hz),2.57-2.66 (2H, m), 2.64 (2H, s), 2.68-2.73 (1H, m) 2.81 (1H, d, J=15.8Hz), 2.90 (1H, d, J=15.4 Hz), 3.20 (1H, t, J=15.8 Hz), 3.65 (3H, s),6.62 (1H, dt, J=6.7, 1.8 Hz), 7.00-7.07 (5H, m), 7.21 (1H, dd, J=6.7,1.8 Hz), 7.44 (1H, d, J=6.7 Hz), 7.48 (1H, brs)

Mass (EI): 402 (M⁺)

Similarly, 2-benzyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo-[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using2-benzyl-4aα(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,5,6,7,8,8a-decahydroisoquinolinerespectively instead of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using o-tollyl hydrazine instead of phenyl hydrazine andrespectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using m-tollyl hydrazine instead of phenyl hydrazine andrespectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using o-tollyl hydrazine instead of phenylhydrazine andrespectively using 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 4-chlorophenylhydrazine instead of phenylhydrazine and respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo-[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo-[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo-[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo-[2,3-g]isoquinolineare produced by using 3-chlorophenyl hydrazine instead of phenylhydrazine and respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 2-chlorophenylhydrazine instead of phenylhydrazine and respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 4-fluorophenylhydrazine instead of phenylhydrazine and respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-20-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-fluorophenylhydrazine instead of phenylhydrazine and respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,are produced by using 2-fluorophenyl hydrazine instead of phenylhydrazine and respectively using2-cyclopropylmethy-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,(2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 4-bromophenylhydrazine instead of phenylhydrazineand respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and 2-allyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline are producedby using 3-bromophenylhydrazine instead of phenylhydrazine andrespectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and1-allyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 2-bromophenyl hydrazine instead of phenylhydrazine and respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline, and2-allyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 4-nitrophenylhydrazine instead of phenylhydrazineand respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-methyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 3-nitrophenylhydrazine instead of phenylhydrazineand respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using 2-nitrophenylhydrazine instead of phenylhydrazineand respectively using2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineare produced by using phenylmethylhydrazine instead of phenylhydrazineand respectively using 2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,5,6,7,8,8a-decahydroisoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

EXAMPLE 452-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline56 ##STR63##

A solution of 70 mg (0.17 mmol) of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolinein 2 ml of anhydrous DMF was caused to react with 0.12 ml (1.3 mmol) ofpropane thiol and 98 mg (0.87 mmol) of potassium-t-butoxide at 150° C.for three hours. Since the reaction mixture still contained unalteredreactants, it was caused to react further with 0.06 ml (0.7 mmol) ofpropane thiol and 49 mg (0.44 mmol) of potassium-t-butoxide for twohours and then with 0.12 mol (1.3 mmol) of propane thiol and 98 mg (0.07mmol) of potassium-t-butoxide for two hours. The resultant reactionmixture was distilled under a vacuum to expel the solvent, combined with8 ml of a saturated aqueous solution of sodium hydrogen carbonate, andextracted three times from 8 ml of ethanol/chloroform (3/1). The extractwas washed with a saturated aqueous saline solution, dried,concentrated, and refined by silica gel column chromatograph (9385, 7 g;chloroform - ammonia-saturated chloroform - 5%methanol/ammonia-saturated chloroform), to afford 39.7 mg of thecaptioned compound (yield 59%). This compound was dissolved in 2 ml ofchloroform and 0.2 ml of methanol and isolated as the methanesulfonateby addition of methanesulfonic acid.

m.p.: 153° to 157° C. (methanesulfonate)

Mass (EI): 388 (M⁺)

Elementary analyses

    ______________________________________                                        For C.sub.25 H.sub.28 N.sub.2 O.sub.2 CH.sub.3 SO.sub.3 H1.5H.sub.2 O                   C    H           N      S                                           ______________________________________                                        Calculated  61.04  6.90        5.47 6.27                                      Found       60.95  6.73        5.34 6.31                                      ______________________________________                                    

Similarly,2-benzyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-hydroxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6-methyl-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6-methyl-indolo[2,3-g]isoquinoline,and2-allyl-4aα-(3-hydroxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6-methyl-indolo[2,3-g]isoquinolineare produced by respectively using2-benzyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-10-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-methyl-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-ocotahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-chloro-11aβ-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-10-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-chloro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-10-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-fluoro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-10-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-bromo-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-9-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-8-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-10-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-allyl-4aα-(3-methoxyphenyl)-7-nitro-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-benzyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline,and 2-allyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinolineinstead of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-11aβ-hydroxy-1,2,3,4,4a,5,11,11a-octahydro-6H-indolo[2,3-g]isoquinoline.

REFERENTIAL EXAMPLE 122-(2,2,2-Trichloroethoxycarbonyl)-4a-(3-methoxyphenyl)-6-acetoxy-2,3,4,4a,5,6,7,8-octahydroisoquinoline57 ##STR64##

In an atmosphere of argon, 19.5 g of2-methyl-4aα-(3-methoxyphenyl)-6-acetoxy-2,3,4,4a,5,6,7,8-octahydroisoquinolinewas dissolved in 100 ml of 1,2-dichloroethane and 6.6 g of proton spongewas added to the produced solution. At 0° C., 12.8 ml of2,2,2-trichloroethylchloroformate was added dropwise to the resultantmixture. The suspension consequently obtained was heated to roomtemperature and stirred for 15 hours. The resultant reaction mixture wasdistilled under a vacuum to expel the solvent, combined with 400 ml ofether, and washed two times with 150 ml of 1N hydrochloric acid, thenwith 100 ml of a saturated aqueous saline solution, dried, and refinedby silica gel column chromatography cyclohexane/ethyl acetate=10:1-5:1),to afford 21.2 g of the captioned compound (6-position acetoxy mixture)(yield 72%).

Partially separated 6-position acetoxy isomers were subjected tospectral analysis.

Highly polar component (6-α acetoxy form)

IR (liquid film method) cm⁻¹ : 3024, 1717, 1415, 1255, 1216, 758

NMR (CDCl₃, 400 MHz) α: 1.31 (3H, d, J=4.8 Hz), 1.57-1.65 (2H, m),1.75-1.86 (2H, m), 1.98-2.06 (1H, m), 2.14-2.23 (1H, m) 2.63-2.74 (1H,m), 2.77-2.88 (1H, m), 3.08 (1H, d, J=15.1 Hz), 3.80 (3H, s), 3.82-3.89(1H, m), 4.67-4.85 (2H, m), 4.98 (1H, s), 6.70 (1H, dd, J=6.3, 2.0 Hz),6.80 (1H, dd, J=2.5, 1.9 Hz), 6.85 (1H, d, J=7.8 Hz), 7.01 (1H, d, J=7.8Hz), 7.22 (1H, t, J=7.8 Hz)

Mass (EI): 475 (M⁺¹)

High-resolving mass spectrum: For C₂₁ H₂₄ O₅ NC₁₃ : Calculated 475.0720.Found 475.0716.

Lowly polar component (6β acetoxy form)

IR (liquid film method) cm⁻¹ : 2954, 1725, 1410, 1251, 1141, 1046, 754

NMR (CDCl₃, 400 MHz) δ: 1.39-1.53 (2H, m), 1.83-2.09 (3H, m), 2.02 (3H,s), 2.25-2.30 (2H, m), 2.83-3.07 (2H, m), 3.82 (3H, s), 3.85-3.95 (1H,m), 4.54-4.61 (1H, m), 4.70-4.88 (2H, m), 6.77 (1H, dd, J=7.8, 2.4 Hz),6.91-6.95 (2H, m), 6.98 (1H, d, J=9.3 Hz), 7.27 (1H, t, J=7.8 Hz)

Mass (EI): 475 (M⁺)

High-resolving mass spectrum: For C₂₁ H₂₃ O₅ NC₁₂ : Calculated 475.0720.Found 475.0718.

EXAMPLE 462-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-acetoxy-8a.beta.-hydroxy-1,1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline58 ##STR65##

In an atmosphere of argon, 16.5 g of2-(2,2,2-trichloroethoxycarbonyl)-4a-(3-methoxyphenyl)-6-acetoxy-2,3,4,4a,5,6,7,8-octahydroisoquinolinewas dissolved in 200 ml of methylene chloride and the produced solutionwas cooled to 0° C. The cooled solution was caused to react with 8.6 gof m-chlorobenzoic acid for 1.5 hours. The reaction solutionconsequently obtained was distilled to expel the solvent. The soliddistillate was used in its unmodified form for the following reaction.

The crude produce was dissolved in 150 ml of acetic acid and cooled to0° C. and sodium borohydride was added piecemeal to the cooled solution.The resultant reaction mixture was heated to room temperature and leftreacting for 15 minutes. The reaction solution was distilled under avacuum to expel the acetic acid, combined with 300 ml of a saturatedaqueous solution of sodium hydrogen carbonate, and extracted three timesfrom 200 ml of ethyl acetate. The extract was dried with sodium sulfate,distilled under a vacuum to expel the solvent, and refined by silica gelcolumn chromatograph (chloroform), to produce 10.8 g of the captionedcompound (6-position acetoxy mixture) (yield 63%). The partiallyseparatedless polar component was subjected to spectral analysis.

IR (liquid film method) cm⁻¹ : 3462, 2958, 1715, 1605, 1582, 1437, 1249,1033, 758

NMR (CDCl₃, 90 MHz) δ: 1.55-1.65 (2H, m), 1.65-1.85 (2H, m), 1.92 (3H,s), 1.97-2.18 (2H, m), 2.20-2.57 (3H, m), 3.50 (1H, t, J=7.8 Hz), 3,79(3H, s), 3.80-3.95 (2H, m), 4.78 (2H, d, J=6.5 Hz), 5.10-5.30 (1H, m),6.68-6.84 (2H, m), 6.92-7.25 (2H, m)

Mass (EI): 493 (M⁺).

EXAMPLE 472-Methyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline59 ##STR66##

In an atmosphere of argon, 1.5 g of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-acetoxy-8aα-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinewas dissolved in 20 ml of anhydrous THF and 0.35 g of lithium aluminumhydride was added to the produced solution. The resultant mixture wasleft reacting at room temperature for 30 minutes and then cooled to 0°C. The reaction mixture, after assuming a solidified state inconsequence of gradual dropwise addition of a saturated aqueous solutionof Rochelle salt, was thoroughly stirred with 20 ml of chloroform andthen filtered through a bed of celite. The residue was thoroughly washedwith chloroform. The filtrate and the washings were combined andconcentrated under a vacuum. The concentrate was refined by silica gelcolumn chromatography (chloroform - ammonia-saturated chloroform - 5%methanol/ammonia-saturated chloroform), to produce 0.63 g of thecaptioned compound (71%, 6-hydroxy mixture).

IR (KBr) cm⁻¹ : 3412, 1599, 1493, 1236, 1071, 893, 795, 723, 540

Mass (EI): 291 (M⁺).

EXAMPLE 482-Methyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline60 ##STR67##

In an atmosphere of argon, 0.19 ml of oxalyl chloride was dissolved in12 ml of anhydrous methylene chloride and the produced solution wascooled to -55° C. The cooled solution and 1.5 ml of a solution of DMSOin methylene chloride gradually added cropwise thereto were stirred atthe same temperature for two minutes. The produced mixture and asolution of 0.5 g of2-methyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinein 2 ml of methylene chloride added dropwise thereto and 2 ml ofmethylene chloride as a cleaning liquid similarly added thereto werestirred at -55° C. for 30 minutes. The resultant mixture and 1.2 ml oftriethylamine added thereto were heated to room temperature. Theproduced reaction mixture was subjected to phase separation by theaddition of 20 ml of distilled water. The aqueous phase consequentlyseparated was further extracted two times from 12 ml of methylenechloride. The organic layers were combined, washed with 10 ml of asaturated aqueous saline solution, dried, and then concentrated. Whenthe concentrate was refined by silica gel column chromatography(chloroform - 2% methanol/chloroform - 5% methanol/chloroform), 0.45 gof the captioned compound (yield 91%) was obtained. This compound, onbeing recrystallized from n-hexane-ethyl acetate, produced 0.38 g of apure product of the compound (m.p. 96° to 97° C.) (yield 77%).

IR (Kbr) cm⁻¹ : 3406, 2944, 1711, 1605, 1578, 1452, 1257, 1114, 1038,895, 774, 708

NMR (CDCl₃, 400 MHz) δ: 1.85-1.93 (2H, m), 2.15-2.32 (3H, m), 2.33 (3H,s), 2.55 (2H, t, J=11.0 Hz), 2.62-2.66 (1H, m), 2.77 (1H, d, J=11.0 Hz),2.79-2.86 (1H, m), 3.13 (1H, d, J=14.6 Hz), 3.78 (3H, s), 6.72 (1H, dd,J=7.4, 3.0 Hz), 6.96-6.97 (2H, m), 7.21 (1H, t, J=8.5 Hz)

Mass (EI): 289 (M⁺).

EXAMPLE 494aα-(3-Methoxyphenyl)-6-acetone-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline61 ##STR68##

In an atmosphere or argon, 2.04 g of2-(2,2)-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-6-acetoxy-8a.beta.-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinewas disssolved in 50 ml of acetic acid and the produced solution wascombined with 2.70 g of zinc dust. The resultant suspension was stirredat room temperature for four hours and passed through celite to removeimpurities originating in zinc. The impurities were thoroughly washedwith acetic acid. The washing and the filtrate were combined anddistilled under a vacuum to expel acetic acid. The distillate wascombined with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate, extracted three times from 50 ml of chloroform, and washedwith 50 ml of a saturated aqueous saline solution. The washed extractwas dried, concentrated, and refined by silica gel column chromatography(chloroform - 5% methanol/ammonia-saturated chloroform), to afford 0.95g of the captioned compound (6-position acetoxy mixture) (yield 72%).

IR (liquid film method) cm⁻¹ : 3360, 2936, 1712, 1607, 1582, 1455, 1248,1053, 888, 713

Mass (EI): 319 (M⁺).

EXAMPLE 502-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline62 ##STR69##

In an atmosphere of argon, 0.68 g of4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinewas dissolved in 15 ml of anhydrous 1,2-dichloroethane and the producedsolution was combined with 0.46 g of proton sponge and 0.29 ml ofcyclopropanecarbonyl chloride. The resultant mixture was distilled undera vacuum to expel the solvent, combined with 20 ml of ether, and washedwith 20 ml of 1N hydroxhloric acid and 10 ml of a saturated aqueoussaline solution. The washed distillate was dried and concentrated toafford the captioned compound in an oily state (crude yield 91%), whichwas used in its unmodified form in the following reaction.

IR (liquid film method) cm⁻¹ : 3430, 2944, 1702, 1605, 1582, 1453, 1240,1029, 750

MASS (EI): 387 (M⁺).

Similarly,2-benzoyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenylacetyl-4aα-(3-methoxyphenyl)-6-acetoxyl-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and 2-acryloyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline are produced by usingbenzoyl chloride, phenylacetyl chloride, and acryloyl chloriderespectively instead of cyclopropanecarbonyl chloride.

EXAMPLE 512-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline63 ##STR70##

In an atmosphere of argon, the2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolineobtained in Example 50 was dissolved in 20 ml of anhydrous THF and theproduced solution was combined with 0.24 g of lithium aluminumhydroxide, left reacting at 0° C. for two hours and at room temperaturefor one hour, and combined slowly with 5 ml of a saturated aqueoussolution of a Rochelle salt. The resultant reaction mixture was combinedwith 50 ml of chloro-form, filtered through a bed of sellaite, washedwith chloroform, and concentrated, to afford the captioned compound inan oily state (crude yield 85%), which was put to the following reactionin its unmodified form.

IR (liquid film method) cm⁻¹ : 3425, 2940, 1607, 1582, 1444, 1292, 1091,880, 753

MASS (EI): 331 (M⁺).

Similarly,2-benzyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and 2-allyl-4aα-(3-methoxyphenyl)-6-,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline are produced by using2-benzoyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenylacetyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-acryloyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinerespectively instead of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-6-acetoxy-8aβ-hydroxy-1,2,3,4a,5,6,7,8,8a-decahydroisoquinoline.

EXAMPLE 522-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline64 ##STR71##

In an atmosphere of argon, 0.15 ml of oxalyl chloride in 10 ml ofanhydrous methylene chloride and the produced solution was cooled to-55° C. The resultant cooled solution and a solution of 0.24 ml of DMSOin 1 ml of anhydrous methylene chloride added slowly dropwise theretowere left reacting at -55° C. for two minutes. To the resultant reactionmixture, a solution of the2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolineobtained in Example 51 in 2 ml of anhydrous methylene chloride was addedand 2 ml of a washing liquid was similarly added. The resultant mixturewas left reacting at -55° C. for 30 minutes, combined with 1.09 ml oftriethylamine, and heated to room temperature. The mixture was subjectedphase separation by addition of 15 ml of distilled water. The aqueouslayer consequently separated was further extracted from 10 ml ofmethylene chloride. The organic layers consequently separated werecombined, washed with 10 ml of a saturated aqueous saline solution,dried, concentrated, and refined by silica gel column chromatography(chloroform - 2% methanol/chloroform), to afford 0.48 g of the captionedcompound (three steps, yield 68%).

IR (liquid film method) cm⁻¹ : 3404, 2940, 1711, 1605, 1582, 1493, 1429,1241, 1038, 897, 756

NMR (CDCl₃, 400 MHz) δ: 0.11 (2H, d, J=5.9 Hz), 0.50-0.55 (2H, m),0.81-0.89 (1H, m), 1.86-1.90 (2H, m), 2.25-2.28 (2H, m), 2.32-2.37 (3H,m), 2.39-2.46 (1H, m), 2.53 (1H, d, J=14.3 Hz), 2.75-2.87 (4H, m), 3.14(1H, d, J=14.3 Hz), 3.77 (3H, s), 6.70-6.72 (1H, m), 6.97-6.98 (2H, m),7.20 (1H, t, J=8.8 Hz)

Mass (EI): 329 (M⁺)

High-resolution mass spectrum: For C₂₁ H₂₇ O₃ N: Calculated 329.1991.Found 329.1955.

Similarly,2-benzyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6-oxo-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolineare produced by using2-benzyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,2-phenethyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline,and2-allyl-4aα-(3-methoxyphenyl)-6,8aα-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinerespectively instead of2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-6,8aβ-dihydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

REFERENTIAL EXAMPLE 132-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydroisoquinoline65 ##STR72##

In an atmosphere of argon, 1.41 g of2-methyl-4aα-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydroisoquinolinewas dissolved in 15 ml of 1,2-dichloroethane and 0.59 g of proton spongewas added to the produced solution. To the mixture, 1.13 ml of2,2,2-trichloroethyl chloroformate was added dropwise. The suspensionconsequently formed was heated to room temperature and then stirred for24 hours. The resultant reaction mixture was distilled under a vacuum toexpel the solvent, combined with 15 ml of ether, washed two times (10ml, 6 mlxz) of 1N hydrochloric acid, and further washed with 10 ml of asaturated aqueous saline solution, dried, and refined by silica gelcolumn chromatography (cyclohexane/ethyl acetate=5:1), to produce 2.30 gof the captioned compound (yield 100%).

IR (liquid film method) cm⁻¹ : 2936, 1763, 1717, 1667, 1607, 1582, 1412,1125, 1054, 820, 706

NMR (CDCl₃, 400 MHz) δ: 1.15-1.25 (1H, m), 1.26-1.27 (1H, m), 1.40 -1.49(1H, m), 1.52-1.60 (1H, m), 1.66-1.72 (1H, m), 1.80-1.93 (2H, m),2.15-2.21 (2H, m), 2.56 (1H, d, J=13.4 Hz), 2.90-3.01 (1H, m), 3.80 (3H,s), 3.83-3.90 (1H, m), 4.79-4.88 (2H, m), 6.75 (1H, dd, J=7.9, 2.5 Hz),6.87 (1H, s), 6.92 (2H, d, J=8.5 Hz), 7.26 (1H, t, J=7.9 Hz)

Mass (EI): 417 (M⁺).

Similarly,2-(2,2,2-trichloroethoxycarbonyl-4aα-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineis produced by using2-methyl-4aα-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineinstead of2-methyl-4aα-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydroisoquinoline.

EXAMPLE 532-(2,2,2-Trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline66 ##STR73##

In an atmosphere of argon, 0.94 g of2-(2,2,2-trichloroethoxycarbonyl)-4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8,8a-octahydroisoquinolinewas dissolved in 20 ml of methylene chloride and the produced solutionwas cooled to 0° C. The cooled solution was caused to react with 0.55 gof m-chloroperbenzoic acid for 15 minutes. The resultant solid productwas put in its unmodified form to the following reaction.

The crude produce obtained above was dissolved in 20 ml of acetic acidand cooled to 0° C. and sodium borohydride was added piecemeal to thecooled product. The resultant mixture was heated to room temperature andleft reacting for five minutes. The resultant reaction mixture wasdistilled under a vacuum to expel acetic acid, combined with 20 ml of asaturated aqueous solution of sodium hydrogen carbonate, and extractedtwo times from 20 ml of ethyl acetate. The organic layers consequentlyseparated were combined and washed with 15 ml of a saturated aqueoussaline solution. The extract was dried with sodium sulfate, distilledunder a vacuum to expel the solvent, and refined by silica gel columnchromatography (chloroform), to produce 0.73 g of the captioned compound(yield 74%).

IR (liquid film method) cm⁻¹ : 3460, 2934, 1705, 1607, 1582, 1444, 1245,1127, 994, 882, 758

NMR (CDCl₃, 400 MHz) δ: 0.90-1.01 (1H, m), 1.33-1.40 (1H, m), 1.52-1.60(2H, m), 1.67-1.76 (2H, m), 1.80-1.90 (1H, m), 2.05-2.12 (1H, m),2.20-2.40 (2H, m), 2.48-2.63 (1H, m), 3.81 (3H, m), 3.86-4.00 (3H, m),4.73 (2H, s), 6.73 (1H, dd, J=8.6, 2.5 Hz), 7.03 (1H, s), 7.06 (1H, d,J=7.9 Hz), 7.24 (1H, t, J=7.9 Hz)

Mass (EI): 435 (M⁺).

Similarly,2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineis produced by using2-(2,2,2-trichloroethoxycarbonyl)-4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineinstead of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydroisoquinoline.

EXAMPLE 544aα-(3-Methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline67 ##STR74##

A solution of 330 mg of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinewas dissolved in 12 ml of an aqueous 90% acetic acid solution and theproduced solution was caused to react with 0.37 g of zinc at a roomtemperature for 3 hours and then at 50° C. for 15 minutes. The resultantsolution was distilled under a vacuum to expel acetic acid, combinedwith 15 ml of a saturated aqueous solution of sodium hydrogen carbonateand 15 ml of chloroform, and filtered through a bed of celite. Thefiltrate was subjected to phase separation and extracted two times from10 ml of chloroform. The organic layers consequently separated werecombined, washed with 15 ml of a saturated aqueous saline solution,dried, concentrated, and refined by silica gel column chromatography(chloroform - 5% methanol/chloroform), to afford 164 mg of the captionedcompound (yield 83%).

IR (liquid film method) cm⁻¹ : 3358, 2938, 1607, 1582, 1452, 1249, 1054,886, 712

NMR (CDCl₃, 400 MHz) δ: 0.87-0.98 (1H, m), 1.31-1.37 (1H, m), 1.48-1.55(2H, m), 1.63-1.71 (2H, m), 1.80-1.92 (1H, m), 2.10-2.19 (2H, m), 2.27(1H, dt, J=13.4, 5.5 Hz), 2.35 (1H, dt, J=12.8, 1.8 Hz), 2.54 (1H, d,J=11.0 Hz), 2.64 (1H, d, J=11.6 Hz), 3.59 (1H, d, J=11.0 Hz), 3.81 (3H,s), 6.69 (1H, dd, J=7.9, 2.4 Hz), 7.06-7.09 (2H, m), 7.21 (1H, t, J=7.9Hz)

Mass (EI): 261 (M⁺).

Similarly,4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineby using2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineinstead of2-(2,2,2-trichloroethoxycarbonyl)-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

EXAMPLE 552-Cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline68 ##STR75##

A solution of 164 mg of4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolinein 5 ml of anhydrous 1,2-dichloroethane was combined with 134 mg ofproton sponge.

The produced mixture was caused to react with 0.14 ml of cyclopropylcarbonyl chloride at room temperature for 30 minutes. The resultantreaction solution was distilled under a vacuum to expel the solvent,combined with 15 ml of ether, and washed two times with 10 ml of 1Nhydrochloric acid and further with 10 ml of a saturated aqueous salinesolution. The washed distillate was dried and distilled under a vacuumto expel the solvent. The crude product was subjected to azeotropicdistillation with chloroform-toluene. The azeotropic mixtureconsequently obtained (0.20 g and 97% in yield) was used in thefollowing reaction.

IR (liquid film method) cm⁻¹ : 3426, 2940, 1700, 1605, 1456, 1245, 1031,886, 756

Mass (EI): 329 (M⁺).

Similarly,2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineis produced by using4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineinstead of4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

EXAMPLE 562-Cyclopropylmethyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline69 ##STR76##

In 5 ml of anhydrous THF, 0.19 g of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolineobtained in a crude form in Example 112 was dissolved. The producedsolution was cooled to 0° C. and caused to react with lithium aluminumhydride at 0° C. for 15 minutes and then at room temperature for onehour. The resultant reaction solution, after being solidified inconsequence of gradual addition of 0.5 ml of a saturated aqueoussolution of Rochelle salt, was suspended in chloroform. The suspensionwas filtered through a bed of celite. The filtrate was distilled under avacuum to expel the solvent and refined by silica gel columnchromatography (chloroform - ammonia-saturated chloroform), to afford0.14 g of the captioned compound (yield 77%).

IR (liquid film method) cm⁻¹ : 3426, 2938, 1607, 1582, 1456, 1290, 1093,1052, 1031, 884, 756

NMR (CDCl₃, 400 MHz) δ: 0.02-0.08 (2H, m), 0.42-0.51 (2H, m), 0.75-0.83(1H, m), 0.83-0.96 (1H, m), 1.30-1.38 (1H, m), 1.48-1.58 (2H, m),1.58-1.92 (5H, m), 2.10-2.32 (4H, m), 2.60-2.68 (2H, m), 2.97 (1H,d,J=10.8 Hz), 3.81 (3H, s), 6.69 (1H, dd, J=8.3 Hz, 1.9 Hz), 7.04-7.08(2H, m), 7.20 (1H, t, J=8.3 Hz)

Mass (EI): 315 (M⁺)

Similarly,2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8aβ-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineis produced by using2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydro-2,2-dimethyl-1,3-dioxolo[4,5-g]isoquinolineinstead of2-cyclopropylcarbonyl-4aα-(3-methoxyphenyl)-8aβ-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline.

EXAMPLE 57

The pharmacological activities of compounds of this invention are shownbelow.

In the test for bonding, the homogenate of the brain of a guinea pigwasdiluted with Tris buffer in a ratio calculated to give to the producedsolution a protein content of 0.7 mg per prot/tube was used asincorporated in the reaction solution. With regard to ligands forbinding assay, 3H-DAGO (μ), DPDPE (δ), and EKC (κ) were used for hotsamples and naloxone (μ), DADLE (δ), and naloxone (κ) for cold samples.

The test of the compounds of this invention for agonist and antagonistactivities was carried out in according to the method proposed byTakemori et al. (Takemori, A, E. et al.: Eur. J. Pharmacal., 1982, 85,163) using Guinea Pig Ileal Longitudinal Muscle Mouse Vas Deferens(MVD).

Table 1 show the pharmacological activities of main compounds. Thesecompounds are antagonists exhibiting very high selectivity for theδ-receptor of opioid. Particularly, the2-cyclopropylmethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydro-6H-indolo[2,3-g]isoquinoline19 (Ki value=3.50) exhibits selectivity twice as high (μ/δ: 100=NTI,205=19) as nartol indol (NTI), a substance which is held to possess thehighest selectivity for the δ-receptor in all currently knownsubstances. This compound avoids affecting the inhibition of contractionof the ileum of a guinea pig, shows a Ke value of 4.80 to DPDPE, apeptide which is highly selective for the δ-receptor in the Mouse VasDeferens, and selectively attenuate the inhibition of contraction byDPDPE. This fact safely supports a conclusion that the indole compoundsrepresented by the compound 19 constitute themselves antagonistsselectively effective on the δ-receptor. PG,223

                                      TABLE 1                                     __________________________________________________________________________    Pharmacological activity of indole derivatives                                __________________________________________________________________________    MVD                                                                                    Antagonism                                                                    to DPDPE   Bonding assay                                             com-                                                                              IC.sub.50                                                                          at 100 nM  Ki value      Ki ratio                                    pound                                                                             (nM) DR   Ke pA2                                                                              μ δ                                                                           κ                                                                            μ/δ                                                                      μ/δ                                                                      κ/μ                        __________________________________________________________________________    2   68600 +                                                                            8.14 140                                                                              6.86                                                                             1650 193 5970<                                                                              8.55                                                                              30.9<                                                                             3.62<                                   7940            (1230-                                                                             (138-                                                                    2340)                                                                              280)                                                 19  28900 +                                                                            (20 nM)-                                                                           4.80                                                                             8.30                                                                             716  3.50                                                                              951  205 272 1.33                                    5640 5.17 5.80                                                                             8.22                                                                             (410-                                                                              (2.78-                                                                            (784-                                                     (50 nM)-   1320)                                                                              4.23)                                                                             1120)                                                     9.62                                                                 4   46100 +                                                                            3.37 422                                                                              6.37                                                                             6420 1240                                                                              11600<                                                                             5.18                                                                              9.35<                                                                             1.81<                                   6780            (4830-                                                                             (938-                                                                    11200)                                                                             1660)                                                6   23600 +                                                                            5.16 240                                                                              6.62                                                                             7090<                                                                              1100                                                                              27400<                                                                             6.45<                                                                             24.9<                                                                             3.86<                                   3460                 (724-                                                                         1680)                                                8   25900 +                                                                            15.0 71.4                                                                             7.15                                                                             4590 59.0                                                                              6750<                                                                              77.8                                                                              114<                                                                              1.47<                                   4520            (4110-                                                                             (48.6-                                                                   5260)                                                                              71.6)                                                10  21900 +         N.D. 1390                                                                              K.D. --  --  --                                      2180                                                                      12  (25000)                                                                            8.27 138                                                                              6.86                                                                             1230 120 380  10.3                                                                              3.17                                                                              0.31                                                    (350-                                                                              (65.1-                                                                            (367-                                                                1940)                                                                              209)                                                                              527)                                             14  32300 +                                                                            2.60 625                                                                              6.20                                                                             N.D. 201 3090 --  15.4                                                                              --                                      2180                 (138-                                                                         200)                                                 25                  1530 2.77                                                                              144  552 52.0                                                                              0.09                                                    (1300-                                                                             (1.25-                                                                            (66.1-                                                               1780)                                                                              6.15)                                                                             365)                                             29       (20 nM)-                                                                           3.83                                                                             8.41                                                                             1180 1.91                                                                              370  618 194 0.31                                         6.22 1.51                                                                             8.82                                                                             (889-                                                                              (1.37-                                                                            (164-                                                     (50 nM)-   1600)                                                                              2.63)                                                                             1080)                                                     34.1                                                                 31       4.84 13.0                                                                             7.89                                                                             (27000)                                                                            2.97                                                                              2240 9090<                                                                             754 0.09                                                         (2.07-                                                                            (886-                                                                     4.32)                                                                             9170)                                            37       8.93 6.31                                                                             8.20                                                                             1550 6.94                                                                              342  223 49.3                                                                              0.22                                                    (1030-                                                                             (3.32-                                                                            (140-                                                                2550)                                                                              22.5)                                                                             1140)                                            40       (20 nM)-                                                                           9.90                                                                             8.00                                                                             1650 8.31                                                                              936  199 113 0.57                                         3.02 2.86                                                                             8.54                                                                             (1420-                                                                             (3.92-                                                                            (770-                                                     (50 nM)-   1900)                                                                              15.1)                                                                             1100)                                                     18.5                                                                 47       (20 nM)-                                                                           5.81                                                                             8.24                                                                             1170 0.37                                                                              388  3160                                                                              1050                                                                              0.33                                         4.44 1.69                                                                             8.77                                                                             (619-                                                                              (0.20-                                                                            (252-                                                     (50 nM)-   2860)                                                                              0.61)                                                                             617)                                                      30.5                                                                 52       7.33 158                                                                              6.80                                                                             (81100)                                                                            135 2280 601 16.9                                                                              0.03                                                         (97.0-                                                                            (785-                                                                     173)                                                                              23200)                                           54  10200 +                                                                            (20 nM)-                                                                           8.13                                                                             8.24                                                                             1430 2.75 +                                                                            662  520 241 0.46                                    1710 14.3 11.3                                                                             8.77                                                                             (597-                                                                              0.47                                                                              (359-                                                     (50 nM)-   53300)   1940)                                                     22.4                                                                 56                  723  1.71                                                                              1550 423 906 2.14                                                    (510-                                                                              (1.15-                                                                            (964-                                                                1050)                                                                              2.46)                                                                             2970)                                            __________________________________________________________________________                               GPI                                                                                Nal-                                                                 com-                                                                              IC.sub.50                                                                          oxone                                                                             nor-BNl                                                          pound                                                                             (nM) DR  DR  Ke pA2                                __________________________________________________________________________                           2   65100                                                                              1.12                                                                              1.25                                                                              301                                                                              6.65                                                          (46500-                                                                            (0.78-                                                                            (0.69-                                                               91100)                                                                             1.60)                                                                             2.45)                                                            19  34600                                                                              0.93                                                                              0.95                                                                 (25800-                                                                            (0.74-                                                                            (0.75-                                                               46400)                                                                             1.17)                                                                             1.21)                                                            4   28000                                                                              0.62                                                                              1.17                                                                 (20000-                                                                            (0.41-                                                                            (0.75-                                                               39100)                                                                             1.03)                                                                             1.21)                                                            6   7900 0.86                                                                              1.23                                                                              77.0                                                                             7.16                                                          (7060-                                                                             (0.69-                                                                            (1.08-                                                               8840)                                                                              1.07)                                                                             1.41)                                                            8   23000                                                                              0.80                                                                              1.04                                                                 (19800-                                                                            (0.62-                                                                            (0.81-                                                               26700)                                                                             1.02)                                                                             1.33)                                                            10  14300                                                                              0.92                                                                              1.31                                                                              64.5                                                                             7.19                                                          (11900-                                                                            (0.66-                                                                            (0.99-                                                               17200)                                                                             1.23)                                                                             1.67)                                                            12  38700                                                                              0.61                                                                              0.70                                                                 (33000-                                                                            (0.51-                                                                            (0.58-                                                               45400)                                                                             0.71)                                                                             0.84)                                                            14  28100                                                                              1.02                                                                              1.27                                                                              74.1                                                                             7.13                                                          (20900-                                                                            (0.83-                                                                            (0.98-                                                               37600)                                                                             1.25)                                                                             1.68)                                                            25  14500                                                                              0.55                                                                              0.77                                                                 (13400-                                                                            (0.40-                                                                            (0.66-                                                               15600)                                                                             0.72)                                                                             0.90)                                                            29  6640 2.50                                                                              2.06                                                                              18.9                                                                             7.72                                                          (5080-                                                                             (0.84-                                                                            (1.25-                                                               8630)                                                                              6.64)                                                                             3.23)                                                            31  20500                                                                              0.93                                                                              0.98                                                                 (17100-                                                                            (0.72-                                                                            (0.74-                                                               24600)                                                                             1.20)                                                                             1.28)                                                            37  10500                                                                              1.19                                                                              1.26                                                                 (8200-                                                                             (0.90-                                                                            (0.73-                                                               13500)                                                                             1.59)                                                                             2.25)                                                            40  11700                                                                              2.17                                                                              2.05                                                                              19.0                                                                             7.72                                                          (8070-                                                                             (1.00-                                                                            (1.37-                                                               16900)                                                                             4.24)                                                                             2.97)                                                            47  64500                                                                              1.06                                                                              1.29                                                                 (26800-                                                                            (0.67-                                                                            (0.85-                                                               155000)                                                                            1.77)                                                                             2.12)                                                            52  16400                                                                              1.06                                                                              1.03                                                                 (13500-                                                                            (0.88-                                                                            (0.85-                                                               20000)                                                                             1.29)                                                                             1.26)                                                            54  5961 1.30                                                                              3.30                                                                              8.70                                                                             8.06                                                          (4430-                                                                             (0.68-                                                                            (1.95-                                                               8021)                                                                              2.72)                                                                             6.78)                                                            56                                                     __________________________________________________________________________

Now, the immunosuppressive activity of the compound 19 which isrepresentative of the compounds of the present invention will be shown.Activity in inhibiting proliferation of mouse T cells by Con-Astimulation

Method of test

A monocellular suspension was prepared by sterilely removing the spleenfrom a mouse and passing the spleen through a mesh. This suspension wasadjusted to a concentration of 5×10⁶ cells/ml and dispensed by the unitof 100 μl in all the individual wells of a96-well plate. The plate sownwith the spleen cells, after having the wells thereof severally fed withConA as a mitogen (of a concentration of 1 μg/ml) in a fixed ratio of 50μl/well and with the compound 19 of a concentration varying ratio (0.1,0.5, 0.75, 1.0, 2.5, 5.0, 7.5, 10, 12.5, 15, 17.5 and 20 μg/ml) in afixed ratio of 50 μl/well, was kept in a CO₂ incubator to have the cellsincubated at 37° C. for 48 hours. Eight hours before completion of theincubation, [³ H]thymidine was added to the contents of the wells in afixed ratio of 2 μCi/10 μl/well. Eight hours after this addition, thecells in the wells were collected on filter papers with the aid of acell harvester. The cells on the filter papers were dried, then combinedwith a toluene type scintillator, and counted for the radioactivity ofthe [³ H] thymidine occluded in the cells by means of a scintillationcounter.

The ratio of suppression of T cell proliferation was calculated inaccordance with the following formula: ##EQU1##

The rate of suppression of T cell proliferation obtained of the compound19 and NTI for comparison are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                       Ratio of suppression of                                        Concentration of                                                                             T cell proliferation, % (n = 3)                                compound (μg/ml)                                                                          19          NTI                                                ______________________________________                                        0.1             6           0                                                 0.5             0           0                                                  0.75           18          0                                                 1.0             1           0                                                 2.5             33          0                                                 5.0             94         15                                                 7.5            100         35                                                 10.0           100         62                                                 12.5           100         85                                                 15.0           100         98                                                 17.5           100         100                                                20.0           100         100                                                ______________________________________                                    

It is noted from the results that the compound 19 exhibited a clearlystrong activity in immunosuppression as elucidated by the comparisonbetween the IC₅₀ value 3 μg/ml of the compound 19 and the IC₅₀ value 8.6μg/ml of NTI.

Other indole derivatives exhibited activities in inhibiting T cellproliferation equal to or higher than the activity of the compound 19 asshown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Activity of indole-skeletoned compound in                                     inhibiting T cell hyperplasia                                                 Compound      IC.sub.50 (μg/ml)                                            ______________________________________                                        19            2.7                                                             25            3.0                                                             29            0.9                                                             31            2.6                                                             37            1.9                                                             40            2.6                                                             47            3.8                                                             52            3.5                                                             56            14.0                                                            ______________________________________                                    

Economic Utility of the Invention

This invention not only contributes to the study of opioid by permittingvery easy and inexpensive supply of δ-opioid receptor antagonists ofhigh selectivity but also offers useful immunity inhibitors.

We claim:
 1. An indole derivative represented by the general formula(1): ##STR77## wherein R₁ stands for alkyl of 1 to 5 carbon atoms,cycloalkylalkyl of 4 to 7 carbon atoms, cycloalkenylalkyl of 5 to 7carbon atoms, aralkyl of 7 to 14 carbon atoms, trans-alkenyl of 4 to 5carbon atoms, allyl, furanyl-2-ylalkyl of 1 to 5 carbon atoms,thienyl-2-ylalkyl of 1 to 5 carbon atoms, vinyloxycarbonyl,trichloroethoxycarbonyl, benzyloxycarbonyl, alkanoyl of 1 to 5 carbonatoms, aralkylcarbonyl of 7 to 14 carbon atoms, 2-furoyl,thiophene-2-carbonyl, cycloalkylcarbonyl of 4 to 7 carbon atoms,alkenylcarbonyl of 3 to 8 carbon atoms, or anisoyl, R₂ for a hydrogenatom, alkyl of 1 to 3 carbon atoms, benzyl, or alkanoyl of 1 to 5 carbonatoms, R₃ for a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, nitro, or alkyl of 1 to 5 carbon atoms, R₄ for a hydrogenatom, alkyl of 1 to 5 carbon atoms, benzyl, or phenyl, and R₅ for ahydrogen atom, hydroxy or alkanoyloxy of 1 to 5 carbon atoms, providingthat said general formula (1) embrances a (+) form, a (-) form, and a(±) form, or a pharmacologically acceptable salt thereof and apharmaceutically acceptable carrier.
 2. An immunorepressing agent havingas an active component thereof an indole derivative as set forth inclaim 1 or a pharmacologically acceptable salt thereof and apharmaceutically acceptable carrier.
 3. The indole derivative defined inclaim 1 wherein R₁ is selected from the group consisting of methyl,ethyl, propyl, butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclopentenylmethyl,cyclohexenylmethyl, allyl, 2-furanylmethyl, 2-thienylmethyl,trans-2-butenyl, cyclopropylcarbonyl, 2,2,2-trichloroethoxycarbonyl andvinyloxycarbonyl.
 4. The indole derivative defined in claim 1 wherein R₂is selected from the group consisting of a hydrogen atom, methyl, ethyl,propyl, benzyl, acetyl, propanoyl, butanoyl and pentanoyl.
 5. The indolederivative defined in claim 1 wherein R₃ is selected from the groupconsisting of a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, nitro, methyl, ethyl, propyl, butyl and pentyl.
 6. Theindole derivative defined in claim 1 wherein R₄ is selected from thegroup consisting of a hydrogen atom, methyl, ethyl, propyl, butyl,pentyl, phenyl and benzyl.
 7. The indole derivative defined in claim 1wherein R₅ is selected from the group consisting of a hydrogen atom,hydroxy, acetoxy, propanoyloxy, butanoyloxy and pentanoyloxy.
 8. Theindole derivative defined in claim 1 represented by the general formula(1): ##STR78## wherein R₁ stands for alkyl of 1 to 5 carbon atoms,cycloalkylalkyl of 4 to 7 carbon atoms, cycloalkenylalkyl of 5 to 7carbon atoms, phenylalkyl of naphthylalkyl of 7 to 14 carbon atoms,trans-alkenyl of 4 to 5 carbon atoms, allyl, furanyl-2-ylalkyl of 1 to 5carbon atoms, thienyl-2-ylalkyl of 1 to 5 carbon atoms,vinyloxycarbonyl, trichloro-ethoxycarbonyl, benzyloxycarbonyl, alkanoylof 1 to 5 carbon atoms, phenylkylcarbonyl or naphthylalkylcarbonyl of 7to 14 carbon atoms, 2-furoyl, thiophene-2-carbonyl, cycloalkylcarbonylof 4 to 7 carbon atoms, alkenylcarbonyl of 3 to 8 carbon atoms, oranisoyl, R₂ for a hydrogen atom, alkyl of 1 to 3 carbon atoms, benzyl,or alkanoyl of 1 to 5 carbon atoms, R₃ for a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, nitro, or alkyl of 1 to 5 carbonatoms, R₄ for a hydrogen atom, alkyl of 1 to 5 carbon atoms, benzyl, orphenyl, and R₅ for a hydrogen atom, hydroxy or alkanoyloxy of 1 to 5carbon atoms, providing that said general formula (1) embrances a (+)form, a (-) form, and a (±) form, or a pharmacologically acceptable saltthereof and a pharmaceutically acceptable carrier.